Secreted and transmembrane polypeptides and nucleic acids encoding the same

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

RELATED APPLICATIONS

This application is a continuation of, and claims priority under 35 USC§210 to, U.S. application 09/665,350 filed Sep. 18, 2000, which is acontinuation-in-part of, and claims priority under 35 USC §120 to, PCTApplication PCT/US00/04414 filed Feb. 22, 2000, which is acontinuation-in-part of, and claims priority under 35 USC §120 to, PCTApplication PCT/US98/19330 filed Sep. 16, 1998, which claims priorityunder 35 USC §119 to U.S. Provisional Application 60/059,122 filed Sep.17, 1997.

FIELD OF THE INVENTION

The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play important roles in, among other things, theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

Secreted proteins have various industrial applications, including aspharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

Membrane-bound proteins and receptors can play important roles in, amongother things, the formation, differentiation and maintenance ofmulticellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell—cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

Membrane-bound proteins and receptor molecules have various industrialapplications, including as pharmaceutical and diagnostic agents.Receptor immunoadhesins, for instance, can be employed as therapeuticagents to block receptor-ligand interactions. The membrane-boundproteins can also be employed for screening of potential peptide orsmall molecule inhibitors of the relevant receptor/ligand interaction.

Efforts are being undertaken by both industry and academia to identifynew, native receptor or membrane-bound proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor or membrane-boundproteins.

1. PRO211 and PRO217

Epidermal growth factor (EGF) is a conventional mitogenic factor thatstimulates the proliferation of various types of cells includingepithelial cells and fibroblasts. EGF binds to and activates the EGFreceptor (EGFR), which initiates intracellular signaling and subsequenteffects. The EGFR is expressed in neurons of the cerebral cortex,cerebellum, and hippocampus in addition to other regions of the centralnervous system (CNS). In addition, EGF is also expressed in variousregions of the CNS. Therefore, EGF acts not only on mitotic cells, butalso on postmitotic neurons. In fact, many studies have indicated thatEGF has neurotrophic or neuromodulatory effects on various types ofneurons in the CNS. For example, EGF acts directly on cultured cerebralcortical and cerebellar neurons, enhancing neurite outgrowth andsurvival. On the other hand, EGF also acts on other cell types,including septal cholinergic and mesencephalic dopaminergic neurons,indirectly through glial cells. Evidence of the effects of EGF onneurons in the CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells is betterunderstood than in postmitotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neurons havesuggested that the EGF-induced neurotrophic actions are mediated bysustained activation of the EGFR and mitogen-activated protein kinase(MAPK) in response to EGF. The sustained intracellular signalingcorrelates with the decreased rate of EGFR down-regulation, which mightdetermine the response of neuronal cells to EGF. It is likely that EGFis a multi-potent growth factor that acts upon various types of cellsincluding mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman,Peptides 12:653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains anintrinsic tyrosine kinase. Stoscheck et al., J. Cell Biochem. 31:135-152(1986). EGF is believed to function by binding to the extracellularportion of its receptor which induces a transmembrane signal thatactivates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain has revealedthe presence of six conserved cysteine residues which cross-bind tocreate three peptide loops, Savage et al., J. Biol. Chem. 248:7669-7672(1979). It is now generally known that several other peptides can reactwith the EGF receptor which share the same generalized motifX_(n)CX₇CX_(4/5)CX₁₀CXCX₅GX₂CX_(n), where X represents any non-cysteineamino acid, and n is a variable repeat number. Non isolated peptideshaving this motif include TGF-α, amphiregulin, schwannoma-derived growthfactor (SDGF), heparin-binding EGF-like growth factors and certainvirally encoded peptides (e.g., Vaccinia virus, Reisner, Nature313:801-803 (1985), Shope fibroma virus, Chang et al., Mol Cell Biol.7:535-540 (1987), Molluscum contagiosum, Porter and Archard, J. Gen.Virol. 68:673-682 (1987), and Myxoma virus, Upton et al., J. Virol.61:1271-1275 (1987), Prigent and Lemoine, Prog. Growth Factor Res.4:1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteins whichhave interesting properties in cell adhesion, protein—proteininteraction and development, Laurence and Gusterson, Tumor Biol.11:229-261 (1990). These proteins include blood coagulation factors(factors VI, IX, X, XII, protein C, protein S, protein Z, tissueplasminogen activator, urokinase), extracellular matrix components(laminin, cytotactin, entactin), cell surface receptors (LDL receptor,thrombomodulin receptor) and immunity-related proteins (complement C1r,uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as in mammaliancells. A number of genes with developmental significance have beenidentified in invertebrates with EGF-like repeats. For example, thenotch gene of Drosophila encodes 36 tandemly arranged 40 amino acidrepeats which show homology to EGF, Wharton et al., Cell 43:557-581(1985). Hydropathy plots indicate a putative membrane spanning domain,with the EGF-related sequences being located on the extracellular sideof the membrane. Other homeotic genes with EGF-like repeats includeDelta, 95F and 5ZD which were identified using probes based on Notch,and the nematode gene Lin-12 which encodes a putative receptor for adevelopmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservationand maintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions, Konturek et al., Eur. J. Gastroenterol Hepatol.7 (10), 933-37 (1995), including the treatment of necrotizingenterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationgastrointestinal ulcerations and congenital microvillus atrophy,Guglietta and Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50(1995). Additionally, EGF has been implicated in hair follicledifferentiation; du Cros, J. Invest. Dermatol. 101 (1 Suppl.), 106S-113S(1993), Hillier, Clin. Endocrinol. 33(4), 427-28 (1990); kidneyfunction, Hamm et al., Semin. Nephrol. 13(1): 109-15 (1993), Harris, Am.J. Kidney Dis. 17(6): 627-30 (1991); tear fluid, van Setten et al., Int.Ophthalmol 15(6); 359-62(1991); vitamin K mediated blood coagulation,Stenflo et al., Blood78(7): 1637-51(1991). EGF is also implicatedvarious skin disease characterized by abnormal keratinocytedifferentiation, e.g., psoriasis, epithelial cancers such as squamouscell carcinomas of the lung, epidermoid carcinoma of the vulva andgliomas. King et al., Am. J. Med. Sci. 296:154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked to developmentalabnormalities and to chronic diseases including cancer. Aaronson,Science 254: 1146-1153 (1991). For example, c-erb-2 (also known asHER-2), a proto-oncogene with close structural similarity to EGFreceptor protein, is overexpressed in human breast cancer. King et al.,Science 229:974-976 (1985); Gullick, Hormones and their actions, Cookeet al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

We herein describe the identification and characterization of novelpolypeptides having homology to EGF, wherein those polypeptides areherein designated PRO211 and PRO217.

2. PRO230

Nephritis is a condition characterized by inflammation of the kidneyaffecting the structure and normal function of the kidney. Thiscondition can be chronic or acute and is generally caused by infection,degenerative process or vascular disease. In all cases, early detectionis desirable so that the patient with nephritis can begin treatment ofthe condition.

An approach to detecting nephritis is to determine the antigensassociated with nephritis and antibodies thereto. In rabbit, atubulointerstitial nephritis antigen (TIN-ag) has been reported inNelson, T. R., et al., J. Biol. Chem., 270(27):16265-70 (July 1995)(GENBANK/U24270). This study reports that the rabbit TIN-ag is abasement membrane glycoprotein having a predicted amino acid sequencewhich has a carboxyl-terminal region exhibiting 30% homology with humanpreprocathepsin B, a member of the cystein proteinase family ofproteins. It is also reported that the rabbit TIN-ag has a domain in theamino-terminal region containing an epidermal growth factor-like motifthat shares homology with laminin A and S chains, alpha 1 chain of typeI collagen, von Willebrand's factor and mucin, indicating structural andfunctional similarities. Studies have also been conducted in mice.However, it is desirable to identify tubulointerstitial nephritisantigens in humans to aid in the development of early detection methodsand treatment of nephritis.

Proteins which have homology to tubulointerstitial nephritis antigensare of particular interest to the medical and industrial communities.Often, proteins having homology to each other have similar function. Itis also of interest when proteins having homology do not have similarfunctions, indicating that certain structural motifs identifyinformation other than function, such as locality of function. We hereindescribe the identification and characterization of a novel polypeptide,designated herein as PRO230, which has homology to tubulointerstitialnephritis antigens.

3. PRO232

Stem cells are undifferentiated cells capable of (a) proliferation, (b)self maintenance, (c) the production of a large number of differentiatedfunctional progeny, (d) regeneration of tissue after injury and/or (e) aflexibility in the use of these options. Stem cells often express cellsurface antigens which are capable of serving as cell specific markersthat can be exploited to identify stem cells, thereby providing a meansfor identifying and isolating specific stem cell populations.

Having possession of different stem cell populations will allow for anumber of important applications. For example, possessing a specificstem cell population will allow for the identification of growth factorsand other proteins which are involved in their proliferation anddifferentiation. In addition, there may be as yet undiscovered proteinswhich are associated with (1) the early steps of dedication of the stemcell to a particular lineage, (2) prevention of such dedication, and (3)negative control of stem cell proliferation, all of which may beidentified if one has possession of the stem cell population. Moreover,stem cells are important and ideal targets for gene therapy where theinserted genes promote the health of the individual into whom the stemcells are transplanted. Finally, stem cells may play important roles intransplantation of organs or tissues, for example liver regeneration andskin grafting.

Given the importance of stem cells in various different applications,efforts are currently being undertaken by both industry and academia toidentify new, native stem cell antigen proteins so as to providespecific cell surface markers for identifying stem cell populations aswell as for providing insight into the functional roles played by stemcell antigens in cell proliferation and differentiation. We hereindescribe the identification and characterization of novel polypeptideshaving homology to a stem cell antigen, wherein those polypeptides areherein designated as PRO232 polypeptides.

4. PRO187

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. However, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factor (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissue, while being apotent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules involves comprehends autocrine (same cell),juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways.Peptide growth factors are elements of a complex biological language,providing the basis for intercellular communication. They permit cellsto convey information between each other, mediate interaction betweencells and change gene expression. The effect of these multifunctionaland pluripotent factors is dependent on the presence or absence of otherpeptides.

FGF-8 is a member of the fibroblast growth factors (FGFs) which are afamily of heparin-binding, potent mitogens for both normal diploidfibroblasts and established cell lines, Gospodarowicz et al. (1984),Proc. Nat. Acad. Sci. USA 81:6963. The FGF family comprises acidic FGF(FGF-1), basic FGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5,FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have twoconserved cysteine residues and share 30-50% sequence homology at theamino acid level. These factors are mitogenic for a wide variety ofnormal diploid mesoderm-derived and neural crest-derived cells,including granulosa cells, adrenal cortical cells, chondrocytes,myoblasts, corneal and vascular endothelial cells (bovine or human),vascular smooth muscle cells, lens, retina and prostatic epithelialcells, oligodendrocytes, astrocytes, chrondocytes, myoblasts andosteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner.

These activities include promotion of cell migration into wound area(chemotaxis), initiation of new blood vessel formulation (angiogenesis),modulation of nerve regeneration and survival (neurotrophism),modulation of endocrine functions, and stimulation or suppression ofspecific cellular protein expression, extracellular matrix productionand cell survival. Baird & Bohlen, Handbook of Exp. Pharmacol. 95(1):369418, Springer, (1990). These properties provide a basis for usingfibroblast growth factors in therapeutic approaches to accelerate woundhealing, nerve repair, collateral blood vessel formation, and the like.For example, fibroblast growth factors have been suggested to minimizemyocardium damage in heart disease and surgery (U.S. Pat. No.4,378,347).

FGF-8, also known as androgen-induced growth factor (AIGF), is a 215amino acid protein which shares 30-40% sequence homology with the othermembers of the FGF family. FGF-8 has been proposed to be underandrogenic regulation and induction in the mouse mammary carcinoma cellline SC3. Tanaka et al., Proc. Natl. Acad. Sci. USA 89:8928-8932 (1992);Sato et al., J. Steroid Biochem. Molec. Biol. 47:91-98 (1993). As aresult, FGF-8 may have a local role in the prostate, which is known tobe an androgen-responsive organ. FGF-8 can also be oncogenic, as itdisplays transforming activity when transfected into NIH-3T3fibroblasts. Kouhara et al., Oncogene 9 455462 (1994). While FGF-8 hasbeen detected in heart, brain, lung, kidney, testis, prostate and ovary,expression was also detected in the absence of exogenous androgens.Schmitt et al., J. Steroid Biochem. Mol. Biol. 57 (34): 173-78 (1996).

FGF-8 shares the property with several other FGFs of being expressed ata variety of stages of murine embryogenesis, which supports the theorythat the various FGFs have multiple and perhaps coordinated roles indifferentiation and embryogenesis. Moreover, FGF-8 has also beenidentified as a protooncogene that cooperates with Wnt-1 in the processof mammary tumorigenesis (Shackleford et al., Proc. Natl. Acad. Sci. USA90, 740-744 (1993); Heikinheimo et al., Mech. Dev. 48:129-138 (1994)).

In contrast to the other FGFs, FGF-8 exists as three protein isoforms,as a result of alternative splicing of the primary transcript. Tanaka etal., supra. Normal adult expression of FGF-8 is weak and confined togonadal tissue, however northern blot analysis has indicated that FGF-8mRNA is present from day 10 through day 12 or murine gestation, whichsuggests that FGF-8 is important to normal development. Heikinheimo etal., Mech Dev. 48(2): 129-38 (1994). Further in situ hybridizationassays between day 8 and 16 of gestation indicated initial expression inthe surface ectoderm of the first bronchial arches, the frontonasalprocess, the forebrain and the midbrain-hindbrain junction. At days10-12, FGF-8 was expressed in the surface ectoderm of the forelimb andhindlimb buds, the nasal its and nasopharynx, the infundibulum and inthe telencephalon, diencephalon and metencephalon. Expression continuesin the developing hindlimbs through day 13 of gestation, but isundetectable thereafter. The results suggest that FGF-8 has a uniquetemporal and spatial pattern in embryogenesis and suggests a role forthis growth factor in multiple regions of ectodermal differentiation inthe post-gastrulation embryo.

We herein describe the identification of novel poypeptides havinghomology to FGF-8, wherein those polypeptides are herein designatedPRO187 polypeptides.

5. PRO265

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December) 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactorβ involvement for treatment for cancer, wound healing andscarring). Also of particular interest is fibromodulin and its use toprevent or reduce dermal scarring. A study of fibromodulin is found inU.S. Pat. No. 5,654,270 to Ruoslahti, et al.

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as fibromodulin, the SLIT protein and plateletglycoprotein V. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound proteins having leucine rich repeats. Weherein describe the identification and characterization of novelpolypeptides having homology to fibromodulin, herein designated asPRO265 polypeptides.

6. PRO219

Human matrilin-2 polypeptide is a member of the von Willebrand factortype A-like module superfamily. von Willebrand factor is a protein whichplays an important role in the maintenence of hemostasis. Morespecifically, von Willebrand factor is a protein which is known toparticipate in platelet-vessel wall interactions at the site of vascularinjury via its ability to interact and form a complex with Factor VIII.The absence of von Willebrand factor in the blood causes an abnormalitywith the blood platelets that prevents platelet adhesion to the vascularwall at the site of the vascular injury. The result is the propensityfor brusing, nose bleeds, intestinal bleeding, and the like comprisingvon Willebrand's disease.

Given the physiological importance of the blood clotting factors,efforts are currently being undertaken by both industry and academia toidentify new, native proteins which may be involved in the coagulationprocess. We herein describe the identification of a novel full-lengthpolypeptide which possesses homology to the human matrilin-2 precursorpolypeptide.

7. PRO246

The cell surface protein HCAR is a membrane-bound protein that acts as areceptor for subgroup C of the adenoviruses and subgroup B of thecoxsackieviruses. Thus, HCAR may provide a means for mediating viralinfection of cells in that the presence of the HCAR receptor on thecellular surface provides a binding site for viral particles, therebyfacilitating viral infection.

In light of the physiological importance of membrane-bound proteins andspecifically those which serve a cell surface receptor for viruses,efforts are currently being undertaken by both industry and academia toidentify new, native membrane-bound receptor proteins. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel receptor proteins.We herein describe a novel membrane-bound polypeptide (designated hereinas PRO246) having homology to the cell surface protein HCAR and tovarious tumor antigens including A33 and carcinoembryonic antigen,wherein this polypeptide may be a novel cell surface virus receptor ortumor antigen.

8. PRO228

There are a number of known seven transmembrane proteins and within thisfamily is a group which includes CD97 and EMR1. CD97 is a seven-spantransmembrane receptor which has a cellular ligand, CD55, DAF. Hamann,et al., J. Exp. Med. (U.S.), 184(3):1189 (1996). Additionally, CD97 hasbeen reported as being a dedifferentiation marker in human thyroidcarcinomas and as associated with inflammation. Aust, et al., CancerRes. (U.S.), 57(9):1798 (1997); Gray, et al., J. Immunol. (U.S.),157(12):5438 (1996). CD97 has also been reported as being related to thesecretin receptor superfamily, but unlike known members of that family,CD97 and EMR1 have extended extracellular regions that possess severalEGF domains at the N-terminus. Hamann, et al., Genomics, 32(1):144(1996); Harmann, et al., J. Immunol., 155(4):1942 (1995). EMR1 isfurther described in Lin, et al., Genomics, 41(3):301 (1997) and Baud,et al., Genomics, 26(2):334 (1995). While CD97 and EMR1 appear to berelated to the secretin receptors, a known member of the secretin familyof G protein-coupled receptors includes the alpha-latroxin receptor,latrophilin, which has been described as calcium independent andabundant among neuronal tissues. Lelianova, et al., J. Biol. Chem.,272(34), 21504 (1997); Davletov, et al., J. Biol. Chem. (U.S.),271(38):23239 (1996). Both members of the secretin receptor superfamilyand non-members which are related to the secretin receptor superfamily,or CRF and calcitonin receptors are of interest. In particular, newmembers of these families, identified by their homology to knownproteins, are of interest.

Efforts are being undertaken by both industry and academia to identifynew membrane-bound receptor proteins, particularly transmembraneproteins with EGF repeats and large N-terminus which may belong to thefamily of seven-transmembrane proteins of which CD97 and EMR1 aremembers. We herein describe the identification and charactization ofnovel polypeptides having homology to CD97 and EMR1, designated hereinas PRO228 polypeptides.

9. PRO533

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. however, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factors (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissues, while beinga potent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules comprehends autocrine (same cell), juxtacrine(neighbor cell), and paracrine (adjacent cell) pathways. Peptide growthfactors are elements of a complex biological language, providing thebasis for intercellular communication. They permit cells to conveyinformation between each other, mediate interaction between cells andchange gene expression. the effect of these multifunctional andpluripotent factors is dependent on the presence or absence of otherpeptides.

Fibroblast growth factors (FGFs) are a family of heparin-binding, potentmitogens for both normal diploid fibroblasts and established cell lines,Godpodarowicz, D. et al. (1984), Proc. Natl. Acad. Sci. USA 81: 6983.the FGF family comprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2(FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8)among others. All FGFs have two conserved cysteine residues and share30-50% sequence homology at the amino acid level. These factors aremitogenic for a wide variety of normal diploid mesoderm-derived andneural crest-derived cells, inducing granulosa cells, adrenal corticalcells, chrondocytes, myoblasts, corneal and vascular endothelial cells(bovine or human), vascular smooth muscle cells, lens, retina andprostatic epithelial cells, oligodendrocytes, astrocytes, chrondocytes,myoblasts and osteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner. These activities include promotion ofcell migration into a wound area (chemotaxis), initiation of new bloodvessel formulation (angiogenesis), modulation of nerve regeneration andsurvival (neurotrophism), modulation of endocrine functions, andstimulation or suppression of specific cellular protein expression,extracellular matrix production and cell survival. Baird, A. & Bohlen,P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These propertiesprovide a basis for using fibroblast growth factors in therapeuticapproaches to accelerate wound healing, nerve repair, collateral bloodvessel formation, and the like. For example, fibroblast growth factors,have been suggested to minimize myocardium damage in heart disease andsurgery (U.S. Pat. No. 4,378,437).

We herein describe the identification and characterization of novelpolypeptides having homology to FGF, herein designated PRO533polypeptides.

10. PRO245

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymes whichregulate levels of protein phosphorylation in the cell. For example, itis known that the transduction of signals that regulate cell growth anddifferentiation is regulated at least in part by phosphorylation anddephosphorylation of various cellular proteins. The enzymes thatcatalyze these processes include the protein kinases, which function tophosphorylate various cellular proteins, and the protein phosphatases,which function to remove phosphate residues from various cellularproteins. The balance of the level of protein phosphorylation in thecell is thus mediated by the relative activities of these two types ofenzymes.

Although many protein kinase enzymes have been identified, thephysiological role played by many of these catalytic proteins has yet tobe elucidated. It is well known, however, that a number of the knownprotein kinases function to phosphorylate tyrosine residues in proteins,thereby leading to a variety of different effects. Perhaps mostimportantly, there has been a great deal of interest in the proteintyrosine kinases since the discovery that many oncogene products andgrowth factors possess intrinsic protein tyrosine kinase activity. Thereis, therefore, a desire to identify new members of the protein tyrosinekinase family.

Given the physiological importance of the protein kinases, efforts arebeing undertaken by both industry and academia to identify new, nativekinase proteins. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel kinase proteins. We herein describe the identification andcharacterization of novel polypeptides having homology to tyrosinekinase proteins, designated herein as PRO245 polypeptides.

11. PRO220, PRO221 and PRO227

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-Alby Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactorβ involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as the SLIT protein and platelet glycoproteinV.

12. PRO258

Immunoglobulins are antibody molecules, the proteins that function bothas receptors for antigen on the B-cell membrane and as the secretedproducts of the plasma cell. Like all antibody molecules,immunoglobulins perform two major functions: they bind specifically toan antigen and they participate in a limited number of biologicaleffector functions. Therefore, new members of the Ig superfamily arealways of interest. Molecules which act as receptors by various virusesand those which act to regulate immune function are of particularinterest. Also of particular interest are those molecules which havehomology to known Ig family members which act as virus receptors orregulate immune function. Thus, molecules having homology to poliovirusreceptors, CRTAM and CD166 (a ligand for lymphocyte antigen CD6) are ofparticular interest.

Extracellular and membrane-bound proteins play important roles in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment, usually at amembrane-bound receptor protein.

We herein describe the identification and characterization of novelpolypeptides having homology to CRTAM, designated herein as PRO258polypeptides.

13. PRO266

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglobular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-Alby Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactorβ involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions, neuronal development and adhesinmolecules. Of particular interest are those proteins having leucine richrepeats and homology to known proteins having leucine rich repeats suchas the SLIT protein. We herein describe novel polypeptides havinghomology to SLIT, designated herein as PRO266 polypeptides.

14. PRO269

Thrombomodulin binds to and regulates the activity of thrombin. It isimportant in the control of blood coagulation. Thrombomodulin functionsas a natural anticoagulant by accelerating the activation of protein Cby thrombin. Soluble thrombomodulin may have therapeutic use as anantithrombotic agent with reduced risk for hemorrhage as compared withheparin. Thrombomodulin is a cell surface trans-membrane glycoprotein,present on endothelial cells and platelets. A smaller, functionallyactive form of thrombomodulin circulates in the plasma and is also foundin urine. (In Haeberli, A., Human Protein Data, VCH Oub., N.Y., 1992).Peptides having homology to thrombomodulin are particularly desirable.

We herein describe the identification and characterization of novelpolypeptides having homology to thrombomodulin, designated herein asPRO269 polypeptides.

15. PRO287

Procollagen C-proteinase enhancer protein binds to and enhances theactivity of bone morphogenic protein “BMP1”/procollagen C-proteinase(PCP). It plays a role in extracellular matrix deposition. BMP1 proteinsmay be used to induce bone and/or cartilage formation and in woundhealing and tissue repair. Therefore, procollagen C-proteinase enhancerprotein, BMP1 and proteins having homology thereto, are of interest tothe scientific and medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to procollagen C-proteinase enhancerprotein precursor and procollagen C-proteinase enhancer protein,designated herein as PRO287 polypeptides.

16. PRO214

Growth factors are molecular signals or mediators that enhances cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. However, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factor β (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissue, while being apotent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules involves comprehends autocrine (same cell),juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways.Peptide growth factors are elements of a complex biological language,providing the basis for intercellular communication. They permit cellsto convey information between each other, mediate interaction betweencells and change gene expression. The effect of these multifunctionaland pluripotent factors is dependent on the presence or absence of otherpeptides.

Epidermal growth factor (EGF) is a conventional mitogenic factor thatstimulates the proliferation of various types of cells includingepithelial cells and fibroblasts. EGF binds to and activates the EGFreceptor (EGFR), which initiates intracellular signaling and subsequenteffects. The EGFR is expressed in neurons of the cerebral cortex,cerebellum, and hippocampus in addition to other regions of the centralnervous system (CNS). In addition, EGF is also expressed in variousregions of the CNS. Therefore, EGF acts not only on mitotic cells, butalso on postmitotic neurons. In fact, many studies have indicated thatEGF has neurotrophic or neuromodulatory effects on various types ofneurons in the CNS. For example, EGF acts directly on cultured cerebralcortical and cerebellar neurons, enhancing neurite outgrowth andsurvival. On the other hand, EGF also acts on other cell types,including septal cholinergic and mesencephalic dopaminergic neurons,indirectly through glial cells. Evidence of the effects of EGF onneurons in the CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells is betterunderstood than in postmitotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neurons havesuggested that the EGF-induced neurotrophic actions are mediated bysustained activation of the EGFR and mitogen-activated protein kinase(MAPK) in response to EGF. The sustained intracellular signalingcorrelates with the decreased rate of EGFR down-regulation, which mightdetermine the response of neuronal cells to EGF. It is likely that EGFis a multi-potent growth factor that acts upon various types of cellsincluding mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, CRPeptides 12:653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains anintrinsic tyrosine kinase. Stoscheck C M et al., J. Cell Biochem.31:135-152 (1986). EGF is believed to function by binding to theextracellular portion of its receptor which induces a transmembranesignal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain has revealedthe presence of six conserved cysteine residues which cross-bind tocreate three peptide loops, Savage C R et al., J. Biol. Chem.248:7669-7672 (1979). It is now generally known that several otherpeptides can react with the EGF receptor which share the samegeneralized motif X_(n)CX₇CX_(4/5)CX₁₀CXCX₅GX₂CX_(n), where X representsany non-cysteine amino acid, and n is a variable repeat number. Nonisolated peptides having this motif include TGF-a, amphiregulin,schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growthfactors and certain virally encoded peptides (e.g., Vaccinia virus,Reisner A H, Nature 313:801-803 (1985), Shope fibroma virus, Chang W.,et al., Mol Cell Biol. 7:535-540 (1987), Molluscum contagiosum, Porter CD & Archard L C, J. Gen. Virol. 68:673-682(1987), and Myxomavirus, UptonC et al. J. Virol. 61:1271-1275 (1987). Prigent S A & Lemoine N. R.,Prog. Growth Factor Res. 4:1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteins whichhave interesting properties in cell adhesion, protein—proteininteraction and development, Laurence D J R & Gusterson B A, Tumor Biol.11:229-261 (1990). These proteins include blood coagulation factors(factors VI, IX, X, XII, protein C, protein S, protein Z, tissueplasminogen activator, urokinase), extracellular matrix components(laminin, cytotactin, entactin), cell surface receptors (LDL receptor,thrombomodulin receptor) and immunity-related proteins (complement C1r,uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as in mammaliancells. A number of genes with developmental significance have beenidentified in invertebrates with EGF-like repeats. For example, thenotch gene of Drosophila encodes 36 tandemly arranged 40 amino acidrepeats which show homology to EGF, Wharton W et al., Cell 43:557-581(1985). Hydropathy plots indicate a putative membrane spanning domain,with the EGF-related sequences being located on the extracellular sideof the membrane. Other homeotic genes with EGF-like repeats includeDelta, 95F and 5ZD which were identified using probes based on Notch,and the nematode gene Lin-12 which encodes a putative receptor for adevelopmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservationand maintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions, Konturek, P C et al., Eur. J. GastroenterolHepatol. 7 (10), 933-37 (1995), including the treatment of necrotizingenterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationgastrointestinal ulcerations and congenital microvillus atrophy, A.Guglietta & P B Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50(1995). Additionally, EGF has been implicated in hair follicledifferentiation; C. L. du Cros, J. Invest. Dermatol. 101 (1 Suppl.),106S-113S (1993), S G Hillier, Clin. Endocrinol. 33(4), 427-28 (1990);kidney function, L. L. Hamm et al., Semin. Nephrol. 13 (1): 109-15(1993), R C Harris, Am. J. Kidney Dis. 17(6): 627-30 (1991); tear fluid,G B van Setten et al., Int. Ophthalmol 15(6); 359-62(1991); vitamin Kmediated blood coagulation, J. Stenflo et al., Blood 78(7): 1637-51(1991). EGF is also implicated various skin disease characterized byabnormal keratinocyte differentiation, e.g., psoriasis, epithelialcancers such as squamous cell carcinomas of the lung, epidermoidcarcinoma of the vulva and gliomas. King, L E et al., Am. J. Med. Sci.296:154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked to developmentalabnormalities and to chronic diseases including cancer. Aaronson S A,Science 254:1146-1153 (1991). For example, c-erb-2 (also known asHER-2), a proto-oncogene with close structural similarity to EGFreceptor protein, is overexpressed in human breast cancer. King et al.,Science 229:974-976 (1985); Gullick, W J, Hormones and their actions,Cooke B A et al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

17. PRO317

The TGF-β supergene family, or simply TGF-β superfamily, a group ofsecreted proteins, includes a large number of related growth anddifferentiation factors expressed in virtually all phyla. Superfamilymembers bind to specific cell surface receptors that activate signaltransduction mechanisms to elicit their multifunctional cytokineeffects. Kolodziejczyk and Hall, Biochem. Cell. Biol., 74:299-314(1996); Attisano and Wrana, Cytokine Growth Factor Rev., 7:327-339(1996); and Hill, Cellular Signaling, 8:533-544 (1996).

Members of this family include five distinct forms of TGF-β (Sporn andRoberts, in Peptide Growth Factors and Their Receptors, Sporn andRoberts, eds. (Springer-Verlag: Berlin, 1990) pp. 419-472), as well asthe differentiation factors vg1 (Weeks and Melton, Cell, 51:861-867(1987)) and DPP-C polypeptide (Padgett et al., Nature, 325:81-84(1987)), the hormones activin and inhibin (Mason et al., Nature318-659-663 (1985); Mason et al., Growth Factors, 1:77-88 (1987)), theMullerian-inhibiting substance (MIS) (Cate et al., Cell, 45: 685-698(1986)), the bone morphogenetic proteins (BMPs) (Wozney et al., Science,242:1528-1534 (1988); PCT WO 88/00205 published Jan. 14, 1988; U.S. Pat.No. 4,877,864 issued Oct. 31, 1989), the developmentally regulatedproteins Vgr-1 (Lyons et al., Proc. Natl. Acad. Sci. USA. 86:45544558(1989)) and Vgr-2 (Jones et al., Molec. Endocrinol., 6:1961-1968(1992)), the mouse growth differentiation factor (GDF), such as GDF-3and GDF-9 (Kingsley, Genes Dev., 8:133-146 (1994); McPherron and Lee, J.Biol. Chem., 268:3444-3449 (1993)), the mouse lefty/Stra1 (Meno et al.,Nature, 381:151-155 (1996); Bouillet et al., Dev. Biol., 170: 420-433(1995)), glial cell line-derived neurotrophic factor (GDNF) (Lin et al.,Science, 260:1130-1132 (1993), neurturin (Kotzbauer et al., Nature,384:467-470 (1996)), and endometrial bleeding-associated factor (EBAF)(Kothapalli et al., J. Clin. Invest., 99:2342-2350 (1997)). The subsetBMP-2A and BMP-2B is approximately 75% homologous in sequence to DPP-Cand may represent the mammalian equivalent of that protein.

The proteins of the TGF-β superfamily are disulfide-linked homo- orheterodimers encoded by larger precursor polypeptide chains containing ahydrophobic signal sequence, a long and relatively poorly conservedN-terminal pro region of several hundred amino acids, a cleavage site(usually polybasic), and a shorter and more highly conserved C-terminalregion. This C-terminal region corresponds to the processed matureprotein and contains approximately 100 amino acids with a characteristiccysteine motif, i.e., the conservation of seven of the nine cysteineresidues of TGF-β among all known family members. Although the positionof the cleavage site between the mature and pro regions varies among thefamily members, the C-terminus of all of the proteins is in theidentical position, ending in the sequence Cys-X-Cys-X, but differing inevery case from the TGF-β consensus C-terminus of Cys-Lys-Cys-Ser. Spornand Roberts, 1990, supra.

There are at least five forms of TGF-β currently identified, TGF-β1,TGF-β2, TGF-β3, TGF-β4, and TGF-β5. The activated form of TGF-β1 is ahomodimer formed by dimerization of the carboxy-terminal 112 amino acidsof a 390 amino acid precursor. Recombinant TGF-β1 has been cloned(Derynck et al., Nature, 316:701-705 (1985)) and expressed in Chinesehamster ovary cells (Gentry et al., Mol. Cell. Biol. 7:3418-3427(1987)). Additionally, recombinant human TGF-β2 (deMartin et al., EMBOJ., 6:3673 (1987)), as well as human and porcine TGF-β3 (Derynck et al.,EMBO J., 7:3737-3743 (1988); ten Dijke et al., Proc. Natl. Acad. Sci.USA, 85:4715 (1988)) have been cloned. TGF-β2 has a precursor form of414 amino acids and is also processed to a homodimer from thecarboxy-terminal 112 amino acids that shares approximately 70% homologywith the active form of TGF-β1 (Marquardt et al., J. Biol. Chem.,262:12127 (1987)). See also EP 200,341; 169,016; 268,561; and 267,463;U.S. Pat. No. 4,774,322; Cheifetz et al., Cell, 48:409-415 (1987);Jakowlew et al., Molecular Endocrin., 2:747-755 (1988); Derynck et al.,J. Biol. Chem., 261:4377-4379 (1986); Sharples et al., DNA, 6:239-244(1987); Derynck et al., Nucl. Acids. Res., 15:3188-3189 (1987); Deryncket al., Nucl. Acids. Res. 15:3187 (1987); Seyedin et al., J. Biol.Chem., 261:5693-5695 (1986); Madisen et al., DNA 7:1-8 (1988); and Hankset al., Proc. Natl. Acad. Sci. (U.S.A.), 85:79-82 (1988).

TGF-β4 and TGF-β5 were cloned from a chicken chondrocyte cDNA library(Jakowlew et al., Molec. Endocrinol., 2:1186-1195 (1988)) and from afrog oocyte cDNA library, respectively.

The pro region of TGF-β associates non-covalently with the mature TGF-βdimer (Wakefield et al., J. Biol. Chem., 263:7646-7654 (1988); Wakefieldet al., Growth Factors, 1:203-218 (1989)), and the pro regions are foundto be necessary for proper folding and secretion of the active maturedimers of both TGF-β and activin (Gray and Mason, Science, 247:1328-1330(1990)). The association between the mature and pro regions of TGF-βmasks the biological activity of the mature dimer, resulting information of an inactive latent form. Latency is not a constant of theTGF-β superfamily, since the presence of the pro region has no effect onactivin or inhibin biological activity.

A unifying feature of the biology of the proteins from the TGF-βsuperfamily is their ability to regulate developmental processes. TGF-βhas been shown to have numerous regulatory actions on a wide variety ofboth normal and neoplastic cells. TGF-β is multifunctional, as it caneither stimulate or inhibit cell proliferation, differentiation, andother critical processes in cell function (Sporn and Roberts, supra).

One member of the TGF-β superfamily, EBAF, is expressed in endometriumonly in the late secretory phase and during abnormal endometrialbleeding. Kothapalli et al., J. Clin. Invest., 99:2342-2350 (1997).Human endometrium is unique in that it is the only tissue in the bodythat bleeds at regular intervals. In addition, abnormal endometrialbleeding is one of the most common manifestations of gynecologicaldiseases, and is a prime indication for hysterectomy. In situhybridization showed that the mRNA of EBAF was expressed in the stromawithout any significant mRNA expression in the endometrial glands orendothelial cells.

The predicted protein sequence of EBAF showed a strong homology to theprotein encoded by mouse lefty/stra3 of the TGF-β superfamily. A motifsearch revealed that the predicted EBAF protein contains most of thecysteine residues which are conserved among the TGF-β-related proteinsand which are necessary for the formation of the cysteine knotstructure. The EBAF sequence contains an additional cysteine residue, 12amino acids upstream from the first conserved cysteine residue. The onlyother family members known to contain an additional cysteine residue areTGF-βs, inhibins, and GDF-3. EBAF, similar to LEFTY, GDF-3/Vgr2, andGDF-9, lacks the cysteine residue that is known to form theintermolecular disulfide bond. Therefore, EBAF appears to be anadditional member of the TGF-β superfamily with an unpaired cysteineresidue that may not exist as a dimer. However, hydrophobic contactsbetween the two monomer subunits may promote dimer formation.Fluorescence in situ hybridization showed that the ebaf gene is locatedon human chromosome 1 at band q42.1.

Additional members of the TGF-β superfamily, such as those related toEBAF, are being searched for by industry and academics. We hereindescribe the identification and characterization of novel polypeptideshaving homology to EBAF, designated herein as PRO317 polypeptides.

18. PRO301

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment. Oneparticular method involves the creation of tumor or cancer specificmonoclonal antibodies (mAbs) which are specific to tumor antigens. SuchmAbs, which can distinguish between normal and cancerous cells areuseful in the diagnosis, prognosis and treatment of the disease.Particular antigens are known to be associated with neoplastic diseases,such as colorectal cancer.

One particular antigen, the A33 antigen is expressed in more than 90% ofprimary or metastatic colon cancers as well as normal colon epithelium.Since colon cancer is a widespread disease, early diagnosis andtreatment is an important medical goal. Diagnosis and treatment of coloncancer can be implemented using monoclonal antibodies (mAbs) specifictherefore having fluorescent, nuclear magnetic or radioactive tags.Radioactive gene, toxins and/or drug tagged mAbs can be used fortreatment in situ with minimal patient description. mAbs can also beused to diagnose during the diagnosis and treatment of colon cancers.For example, when the serum levels of the A33 antigen are elevated in apatient, a drop of the levels after surgery would indicate the tumorresection was successful. On the other hand, a subsequent rise in serumA33 antigen levels after surgery would indicate that metastases of theoriginal tumor may have formed or that new primary tumors may haveappeared. Such monoclonal antibodies can be used in lieu of, or inconjunction with surgery and/or other chemotherapies. For example, U.S.Pat. No. 4,579,827 and U.S. Ser. No. 424,991 (E.P. 199,141) are directedto therapeutic administration of monoclonal antibodies, the latter ofwhich relates to the application of anti-A33 mAb.

Many cancers of epithelial origin have adenovirus receptors. In fact,adenovirus-derived vectors have been proposed as a means of insertingantisense nucleic acids into tumors (U.S. Pat. No. 5,518,885). Thus, theassociation of viral receptors with neoplastic tumors is not unexpected.

We herein describe the identification and characterization of novelpolypeptides having homology to certain cancer-associated antigens,designated herein as PRO301 polypeptides.

19. PRO224

Cholesterol uptake can have serious implications on one's health.Cholesterol uptake provides cells with most of the cholesterol theyrequire for membrane synthesis. If this uptake is blocked, cholesterolaccumulates in the blood and can contribute to the formation ofatherosclerotic plaques in blood vessel walls. Most cholesterol istransported in the blood bound to protein in the form of complexes knownas low-density lipoproteins (LDLs). LDLs are endocytosed into cells viaLDL receptor proteins. Therefore, LDL receptor proteins, and proteinshaving homology thereto, are of interest to the scientific and medicalcommunities.

Membrane-bound proteins and receptors can play an important role in theformation, differentiation and maintenance of multicellular organisms.The LDL receptors are an example of membrane-bound proteins which areinvolved in the synthesis and formation of cell membranes, wherein thehealth of an individual is affected directly and indirectly by itsfunction. Many membrane-bound proteins act as receptors such as the LDLreceptor. These receptors can function to endocytose substrates or theycan function as a receptor for a channel. Other membrane-bound proteinsfunction as signals or antigens.

Membrane-bound proteins and receptor molecules have various industrialapplications, including as pharmaceutical and diagnostic agents. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule regulators of the relevant receptor/ligandinteraction. In the case of the LDL receptor, it is desirable to findmolecules which enhance endocytosis so as to lower blood cholesterollevels and plaque formation. It is also desirable to identify moleculeswhich inhibit endocytosis so that these molecules can be avoided orregulated by individuals having high blood cholesterol. Polypeptideswhich are homologous to lipoprotein receptors but which do not functionas lipoprotein receptors are also of interest in the determination ofthe function of the fragments which show homology.

The following studies report on previously known low density lipoproteinreceptors and related proteins including apolipoproteins: Sawamura, etal., Nippon Chemiphar Co, Japan patent application J09098787; Novak, S.,et al., J. Biol. Chem., 271:(20)11732-6 (1996); Blaas, D., J. Virol.,69(11)7244-7 (November 1995); Scott, J., J. Inherit. Metab. Dis. (UK),9/Supp. 1 (3-16) (1986); Yamamoto, et al., Cell, 39:27-38 (1984);Rebece, et al., Neurobiol., 15:5117 (1994); Novak, S., et al., J. Biol.Chemistry, 271:11732-11736(1996); and Sestavel and Fruchart, Cell Mol.Biol., 40(4):461-81 (June 1994). These publications and others publishedprior to the filing of this application provide further background topeptides already known in the art.

Efforts are being undertaken by both industry and academia to identifynew, native membrane-bound receptor proteins, particularly those havinghomology to lipoprotein receptors. We herein describe the identificationand characterization of novel polypeptides having homology tolipoprotein receptors, designated herein as PRO224 polypeptides.

20. PRO222

Complement is a group of proteins found in the blood that are importantin humoral immunity and inflammation. Complement proteins aresequentially activated by antigen-antibody complexes or by proteolyticenzymes. When activated, complement proteins kill bacteria and othermicroorganisms, affect vascular permeability, release histamine andattract white blood cells. Complement also enhances phagocytosis whenbound to target cells. In order to prevent harm to autologous cells, thecomplement activation pathway is tightly regulated.

Deficiencies in the regulation of complement activation or in thecomplement proteins themselves may lead to immunecomplex diseases, suchas systemic lupus erythematosus, and may result in increasedsusceptibility to bacterial infection. In all cases, early detection ofcomplement deficiency is desirable so that the patient can begintreatment. Thus, research efforts are currently directed towardidentification of soluble and membrane proteins that regulate complementactivation.

Proteins known to be important in regulating complement activation inhumans include Factor H and Complement receptor type 1 (CR1). Factor His a 150 kD soluble serum protein that interacts with complement proteinC3b to accelerate the decay of C3 convertase and acts as a cofactor forFactor I-mediated cleavage of complement protein C4b. Complementreceptor type 1 is a 190-280 kD membrane bound protein found in mastcells and most blood cells. CR1 interacts with complement proteins C3b,C4b, and iC3b to accelerate dissociation of C3 convertases, acts as acofactor for Factor I-mediated cleavage of C3b and C4b, and binds immunecomplexes and promotes their dissolution and phagocytosis.

Proteins which have homology to complement proteins are of particularinterest to the medical and industrial communities. Often, proteinshaving homology to each other have similar function. It is also ofinterest when proteins having homology do not have similar functions,indicating that certain structural motifs identify information otherthan function, such as locality of function.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound proteins, particularly thosehaving homology to known proteins involved in the complement pathway.Proteins involved in the complement pathway were reviewed in BirminghamD J (1995), Critical Reviews in Immunology, 15(2): 133-154 and in AbbasA K, et al. (1994) Cellular and Molecular Immunology, 2nd Ed. W.B.Saunders Company, Philadelphia, pp 295-315.

We herein describe the identification and characterization of novelpolypeptides having homology to complement receptors, designated hereinas PRO222 polypeptides.

21. PRO234

The successful function of many systems within multicellular organismsis dependent on cell—cell interactions. Such interactions are affectedby the alignment of particular ligands with particular receptors in amanner which allows for ligand-receptor binding and thus a cell—celladhesion. While protein—protein interactions in cell recognition havebeen recognized for some time, only recently has the role ofcarbohydrates in physiologically relevant recognition been widelyconsidered (see B. K. Brandley et al., J. Leuk. Biol. 40:97 (1986) andN. Sharon et al., Science 246:227 (1989). Oligosaccharides are wellpositioned to act as recognition novel lectins due to their cell surfacelocation and structural diversity. Many oligosaccharide structures canbe created through the differential activities of a smaller number ofglycosyltransferases. The diverse structures of oligosaccharides can begenerated by transcription of relatively few gene products, whichsuggests that the oligosaccharides are a plausible mechanism by which isdirected a wide range of cell—cell interactions. Examples ofdifferential expression of cell surface carbohydrates and putativecarbohydrate binding proteins (lectins) on interacting cells have beendescribed (J. Dodd & T. M. Jessel, J. Neurosci. 5:3278 (1985); L. J.Regan et al., Proc. Natl. Acad. Sci. USA 83:2248 (1986); M.Constantine-Paton et al., Nature 324:459 (1986); and M. Tiemeyer et al.,J. Biol. Chem. 263:1671 (1989). One interesting member of the lectinfamily are selectins.

The migration of leukocytes to sites of acute or chronic inflammationinvolves adhesive interactions between these cells and the endothelium.This specific adhesion is the initial event in the cascade that isinitiated by inflammatory insults, and it is, therefore, of paramountimportance to the regulated defense of the organism.

The types of cell adhesion molecules that are involved in theinteraction between leukocytes and the endothelium during aninflammatory response currently stands at four: (1) selectins; (2)(carbohydrate and glycoprotein) ligands for selectins; (3) integrins;and (4) integrin ligands, which are members of the immunoglobulin genesuperfamily.

The selectins are cell adhesion molecules that are unified bothstructurally and functionally. Structurally, selectins are characterizedby the inclusion of a domain with homology to a calcium-dependent lectin(C-lectins), an epidermal growth factor (egf)-like domain and severalcomplement binding-like domains, Bevilacqua, M. P. et al., Science243:1160-1165 (1989); Johnston et al, Cell 56:1033-1044 (1989); Lasky etal, Cell 56:1045-1055 (1989); Siegalman, M. et al., Science243:1165-1172 (1989); Stoolman, L. M., Cell 56: 907-910 (1989).Functionally, selectins share the common property of their ability tomediate cell binding through interactions between their lectin domainsand cell surface carbohydrate ligands (Brandley, B, et al., Cell 63,861-863 (1990); Springer, T. and Lasky, L. A., Nature 349, 19-197(1991); Bevilacqua, M. P. and Nelson, R. M., J. Clin. Invest. 91 379-387(1993) and Tedder et al., J. Exp. Med. 170:123-133 (1989).

There are three members identified so far in the selectin family of celladhesion molecules: L-selectin (also called peripheral lymph node homingreceptor (pnHR), LEC-CAM-1, LAM-1, gp90^(MEL), gp100^(MEL), gp110^(MEL),MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, DREG antigen), E-selectin(LEC-CAM-2, LECAM-2, ELAM-1) and P-selectin (LEC-CAM-3, LECAM-3,GMP-140, PADGEM).

The identification of the C-lectin domain has led to an intense effortto define carbohydrate binding ligands for proteins containing suchdomains. E-selectin is believed to recognize the carbohydrate sequenceNeuNAcα2-3Galβ1-4(Fucα1-3)GlcNAc (sialyl-Lewis x, or sLe^(x)) andrelated oligosaccharides, Berg et al., J. Biol. Chem.265:14869-14872(1991); Lowe et al., Cell 63:475-484(1990); Phillips etal., Science 250:1130-1132 (1990); Tiemeyer et al., Proc. Natl. Acad.Sci. USA 88:1138-1142 (1991).

L-selectin, which comprises a lectin domain, performs its adhesivefunction by recognizing carbohydrate-containing ligands on endothelialcells. L-selectin is expressed on the surface of leukocytes, such aslymphocytes, neutrophils, monocytes and eosinophils, and is involvedwith the trafficking of lymphocytes to peripheral lymphoid tissues(Gallatin et al., Nature 303:30-34 (1983)) and with acuteneutrophil-medicated inflammatory responses (Watson, S. R., Nature349:164-167 (1991)). The amino acid sequence of L-selectin and theencoding nucleic acid sequence are, for example, disclosed in U.S. Pat.No. 5,098,833 issued Mar. 24, 1992.

L-selectin (LECAM-1) is particularly interesting because of its abilityto block neutrophil influx (Watson et al., Nature 349:164-167 (1991). Itis expressed in chronic lymphocytic leukemia cells which bind to HEV(Spertini et al., Nature 349:691-694 (1991). It is also believed thatHEV structures at sites of chronic inflammation are associated with thesymptoms of diseases such as rheumatoid arthritis, psoriasis andmultiple sclerosis.

E-selectin (ELAM-1), is particularly interesting because of itstransient expression on endothelial cells in response to IL-1 or TNF.Bevilacqua et al., Science 243:1160 (1989). The time course of thisinduced expression (2-8 h) suggests a role for this receptor in initialneutrophil induced extravasation in response to infection and injury. Ithas further been reported that anti-ELAM-1 antibody blocks the influx ofneutrophils in a primate asthma model and thus is beneficial forpreventing airway obstruction resulting from the inflammatory response.Gundel et al., J. Clin. Invest. 88:1407 (1991).

The adhesion of circulating neutrophils to stimulated vascularendothelium is a primary event of the inflammatory response. P-selectinhas been reported to recognize the Lewis x structure (Galβ1-4(Fucα1-3)GlcNAc), Larsen et al., Cell 63:467-474(1990). Others report that anadditional terminal linked sialic acid is required for high affinitybinding, Moore et al., J. Cell. Biol. 112:491-499 (1991). P-selectin hasbeen shown to be significant in acute lung injury. Anti-P-selectinantibody has been shown to have strong protective effects in a rodentlung injury model. M. S. Mulligan et al., J. Clin. Invest. 90:1600(1991).

We herein describe the identification and characterization of novelpolypeptides having homology to lectin proteins, herein designated asPRO234 polypeptides.

22. PRO231

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymes whichregulate levels of protein phosphorylation in the cell. For example, itis known that the transduction of signals that regulate cell growth anddifferentiation is regulated at least in part by phosphorylation anddephosphorylation of various cellular proteins. The enzymes thatcatalyze these processes include the protein kinases, which function tophosphorylate various cellular proteins, and the protein phosphatases,which function to remove phosphate residues from various cellularproteins. The balance of the level of protein phosphorylation in thecell is thus mediated by the relative activities of these two types ofenzymes.

Protein phosphatases represent a growing family of enzymes that arefound in many diverse forms, including both membrane-bound and solubleforms. While many protein phosphatases have been described, thefunctions of only a very few are beginning to be understood (Tonks,Semin. Cell Biol. 4:373-453 (1993) and Dixon, Recent Prog. Horm. Res.51:405-414 (1996)). However, in general, it appears that many of theprotein phosphatases function to modulate the positive or negativesignals induced by various protein kinases. Therefore, it is likely thatprotein phosphatases play critical roles in numerous and diversecellular processes.

Given the physiological importance of the protein phosphatases, effortsare being undertaken by both industry and academia to identify new,native phosphatase proteins. Many of these efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel phosphatase proteins. Examples of screening methodsand techniques are described in the literature [see, for example, Kleinet al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to acid phosphatases, designated herein asPRO231 polypeptides.

23. PRO229

Scavenger receptors are known to protect IgG molecules from catabolicdegradation. Riechmann and Hollinger, Nature Biotechnology, 15:617(1997). In particular, studies of the CH2 and CH3 domains have shownthat specific sequences of these domains are important in determiningthe half-lives of antibodies. Ellerson, et al., J. Immunol., 116:510(1976); Yasmeen, et al., J. Immunol. 116:518 (1976; Pollock, et al.,Eur. J. Immunol., 20:2021 (1990). Scavenger receptor proteins andantibodies thereto are further reported in U.S. Pat. No. 5,510,466 toKrieger, et al. Due to the ability of scavenger receptors to increasethe half-life of polypeptides and their involvement in immune function,molecules having homology to scavenger receptors are of importance tothe scientific and medical community.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlythose having homology to scavenger receptors. Many efforts are focusedon the screening of mammalian recombinant DNA libraries to identify thecoding sequences for novel secreted and membrane-bound receptorproteins. Examples of screening methods and techniques are described inthe literature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to scavenger receptors, designated hereinas PRO229 polypeptides.

24. PRO238

Oxygen free radicals and antioxidants appear to play an important rolein the central nervous system after cerebral ischemia and reperfusion.Moreover, cardiac injury, related to ischaemia and reperfusion has beenreported to be caused by the action of free radicals. Additionally,studies have reported that the redox state of the cell is a pivotaldeterminant of the fate of the cells. Furthermore, reactive oxygenspecies have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons including for control and prevention of strokes, heartattacks, oxidative stress and hypertension. In this regard, reductases,and particularly, oxidoreductases, are of interest. Publications furtherdescribing this subject matter include Kelsey, et al., Br. J. Cancer,76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40(1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlysecreted proteins which have homology to reductase. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to reductase, designated herein as PRO238polypeptides.

25. PRO233

Studies have reported that the redox state of the cell is an importantdeterminant of the fate of the cell. Furthermore, reactive oxygenspecies have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons, including the control and prevention of strokes, heartattacks, oxidative stress and hypertension. Oxygen free radicals andantioxidants appear to play an important role in the central nervoussystem after cerebral ischemia and reperfusion. Moreover, cardiacinjury, related to ischaemia and reperfusion has been reported to becaused by the action of free radicals. In this regard, reductases, andparticularly, oxidoreductases, are of interest. In addition, thetranscription factors, NF-kappa B and AP-1, are known to be regulated byredox state and to affect the expression of a large variety of genesthought to be involved in the pathogenesis of AIDS, cancer,atherosclerosis and diabetic complications. Publications furtherdescribing this subject matter include Kelsey, et al., Br. J. Cancer,76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40(1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997). Giventhe physiological importance of redox reactions in vivo, efforts arecurrently being under taken to identify new, native proteins which areinvolved in redox reactions. We describe herein the identification ofnovel polypeptides which have homology to reductase, designated hereinas PRO233 polypeptides.

26. PRO223

The carboxypeptidase family of exopeptidases constitutes a diverse groupof enzymes that hydrolyze carboxyl-terminal amide bonds in polypeptides,wherein a large number of mammalian tissues produce these enzymes. Manyof the carboxypeptidase enzymes that have been identified to dateexhibit rather strong cleavage specificities for certain amino acids inpolypeptides. For example, carboxypeptidase enzymes have been identifiedwhich prefer lysine, arginine, serine or amino acids with eitheraromatic or branched aliphatic side chains as substrates at the carboxylterminus of the polypeptide.

With regard to the serine carboxypeptidases, such amino acid specificenzymes have been identified from a variety of different mammalian andnon-mammalian organisms. The mammalian serine carboxypeptidase enzymesplay important roles in many different biological processes including,for example, protein digestion, activation, inactivation, or modulationof peptide hormone activity, and alteration of the physical propertiesof proteins and enzymes.

In light of the physiological importance of the serinecarboxypeptidases, efforts are being undertaken by both industry andacademia to identify new, native secreted and membrane-bound receptorproteins and specifically novel carboxypeptidases. Many of these effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. We describe herein novel polypeptides having homologyto one or more serine carboxypeptidase polypeptides, designated hereinas PRO223 polypeptides.

27. PRO235

Plexin was first identified in Xenopus tadpole nervous system as amembrane glycoprotein which was shown to mediate cell adhesion via ahomophilic binding mechanism in the presence of calcium ions. Strongevolutionary conservation between Xenopus, mouse and human homologs ofplexin has been observed. [Kaneyama et al., Biochem. And Biophys. Res.Comm. 226:524-529 (1996)]. Given the physiological importance of celladhesion mechanisms in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in cell adhesion. Wedescribe herein the identification of a novel polypeptide which hashomology to plexin, designated herein as PRO235.

28. PRO236 and PRO262

β-galactosidase is a well known enzymatic protein which functions tohydrolyze β-galactoside molecules. β-galactosidase has been employed fora variety of different applications, both in vitro and in vivo and hasproven to be an extremely useful research tool. As such, there is aninterest in obtaining novel polypeptides which exhibit homology to theβ-galactosidase polypeptide.

Given the strong interest in obtaining novel polypeptides havinghomology to β-galactosidase, efforts are currently being undertaken byboth industry and academia to identify new, native β-galactosidasehomolog proteins. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel β-galactosidase-like proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. We herein describe novel polypeptides having significanthomology to the β-galactosidase enzyme, designated herein as PRO236 andPRO262 polypeptides.

29. PRO239

Densin is a glycoprotein which has been isolated from the brain whichhas all the hallmarks of an adhesion molecule. It is highly concentratedat synaptic sites in the brain and is expressed prominently in dendriticprocesses in developing neurons. Densin has been characterized as amember of the O-linked sialoglycoproteins. Densin has relevance tomedically important processes such as regeneration. Given thephysiological importance of synaptic processes and cell adhesionmechanisms in vivo, efforts are currently being under taken to identifynew, native proteins which are involved in synaptic machinery and celladhesion. We describe herein the identification of novel polypeptideswhich have homology to densin, designated herein as PRO239 polypeptides.

30. PRO257

Ebnerin is a cell surface protein associated with von Ebner glands inmammals. Efforts are being undertaken by both industry and academia toidentify new, native cell surface receptor proteins and specificallythose which possess sequence homology to cell surface proteins such asebnerin. Many of these efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelreceptor proteins. We herein describe the identification of novelpolypeptides having significant homology to the von Ebner'sgland-associated protein ebnerin, designated herein as PRO257polypeptides.

31. PRO260

Fucosidases are enzymes that remove fucose residues from fucosecontaining proteoglycans. In some pathological conditions, such ascancer, rheumatoid arthritis, and diabetes, there is an abnormalfucosylation of serum proteins. Therefore, fucosidases, and proteinshaving homology to fucosidase, are of importance to the study andabrogation of these conditions. In particular, proteins having homologyto the alpha-1-fucosidase precursor are of interest. Fucosidases andfucosidase inhibitors are further described in U.S. Pat. Nos. 5,637,490,5,382,709, 5,240,707, 5,153,325, 5,100,797, 5,096,909 and 5,017,704.Studies are also reported in Valk, et al., J. Virol., 71(9):6796 (1997),Aktogu, et al., Monaldi. Arch. Chest Dis. (Italy), 52(2): 118(1997) andFocarelli, et al., Biochem. Biophys. Res. Commun. (U.S.), 234(1):54(1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins. Of particularinterest are proteins having homology to the alpha-1-fucosidaseprecursor. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fucosidases, designated herein as PRO260polypeptides.

32. PRO263

CD44 is a cell surface adhesion molecule involved in cell—cell andcell-matrix interactions. Hyaluronic acid, a component of theextracellular matrix is a major ligand. Other ligands include collagen,fibronectin, laminin, chrondroitin sulfate, mucosal addressin, serglycinand osteoponin. CD44 is also important in regulating cell traffic, lymphnode homing, transmission of growth signals, and presentation ofchemokines and growth factors to traveling cells. CD44 surface proteinsare associated with metastatic tumors and CD44 has been used as a markerfor HIV infection. Certain splice variants are associated withmetastasis and poor prognosis of cancer patients. Therefore, moleculeshaving homology with CD44 are of particular interest, as their homologyindicates that they may have functions related to those functions ofCD44. CD44 is further described in U.S. Pat. Nos. 5,506,119, 5,504,194and 5,108,904; Gerberick, et al., Toxicol. Appl. Pharmacol., 146(1):1(1997); Wittig, et al., Immunol. Letters (Netherlands), 57(1-3):217(1997); and Oliveira and Odell, Oral Oncol. (England), 33(4):260 (1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlytransmembrane proteins with homology to CD44 antigen. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to CD44 antigen, designated herein asPRO263 polypeptides.

33. PRO270

Thioredoxins effect reduction-oxidation (redox) state. Many diseases arepotentially related to redox state and reactive oxygen species may playa role in many important biological processes. The transcriptionfactors, NF-kappa B and AP-1, are regulated by redox state and are knownto affect the expression of a large variety of genes thought to beinvolved in the pathogenesis of AIDS, cancer, atherosclerosis anddiabetic complications. Such proteins may also play a role in cellularantioxidant defense, and in pathological conditions involving oxidativestress such as stroke and inflammation in addition to having a role inapoptosis. Therefore, thioredoxins, and proteins having homologythereto, are of interest to the scientific and medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to thioredoxin, designated herein as PRO270polypeptides.

34. PRO271

The proteoglycan link protein is a protein which is intimatelyassociated with various extracellular matrix proteins and morespecifically with proteins such as collagen. For example, one primarycomponent of collagen is a large proteoglycan called aggrecan. Thismolecule is retained by binding to the glycosaminoglycan hyaluronanthrough the amino terminal G1 globular domain of the core protein. Thisbinding is stabilized by the proteoglycan link protein which is aprotein that is also associated with other tissues containing hyaluronanbinding proteoglycans such as versican.

Link protein has been identified as a potential target for autoimmuneantibodies in individuals who suffer from juvenile rheumatoid arthritis(see Guerassimov et al., J. Rheumatology 24(5):959-964 (1997)). As such,there is strong interest in identifying novel proteins having homologyto link protein. We herein describe the identification andcharacterization of novel polypeptides having such homology, designatedherein as PRO271 polypeptides.

35. PRO272

Reticulocalbin is an endoplasmic reticular protein which may be involvedin protein transport and luminal protein processing. Reticulocalbinresides in the lumen of the endopladsmic rerticulum, is known to bindcalcium, and may be involved in a luminal retention mechanism of theendoplasmic reticulum. It contains six domains of the EF-hand motifassociated with high affinity calcium binding. We describe herein theidentification and characterization of a novel polypeptide which hashomology to the reticulocalbin protein, designated herein as PRO272.

36. PRO294

Collagen, a naturally occurring protein, finds wide application inindustry. Chemically hydrolyzed natural collagen can be denatured andrenatured by heating and cooling to produce gelatin, which is used inphotographic and medical, among other applications. Collagen hasimportant properties such as the ability to form interchain aggregateshaving a conformation designated as a triple helix. We herein describethe identification and characterization of a novel polypeptide which hashomology to portions of the collagen molecule, designated herein asPRO294.

37. PRO295

The integrins comprise a supergene family of cell-surface glycoproteinreceptors that promote cellular adhesion. Each cell has numerousreceptors that define its cell adhesive capabilities. Integrins areinvolved in a wide variety of interaction between cells and other cellsor matrix components. The integrins are of particular importance inregulating movement and function of immune system cells The plateletIIb/IIIA integrin complex is of particular importance in regulatingplatelet aggregation. A member of the integrin family, integrin β-6, isexpressed on epithelial cells and modulates epithelial inflammation.Another integrin, leucocyte-associated antigen-1 (LFA-1) is important inthe adhesion of lymphocytes during an immune response. The integrins areexpressed as heterodimers of non-covalently associated alpha and betasubunits. Given the physiological importance of cell adhesion mechanismsin vivo, efforts are currently being under taken to identify new, nativeproteins which are involved in cell adhesion. We describe herein theidentification and characterization of a novel polypeptide which hashomology to integrin, designated herein as PRO295.

38. PRO293

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactors involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known neuronal leucine richrepeat proteins. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound proteins having leucine rich repeats.Examples of screening methods and techniques are described in theliterature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of a novelpolypeptide which has homology to leucine rich repeat proteins,designated herein as PRO293.

39. PRO247

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-Alby Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactors involvement for treatment for cancer, wound healing andscarring).

Densin is a glycoprotein which has been isolated from the brain whichhas all the hallmarks of an adhesion molecule. It is highly concentratedat synaptic sites in the brain and is expressed prominently in dendriticprocesses in developing neurons. Densin has been characterized as amember of the O-linked sialoglycoproteins. Densin has relevance tomedically important processes such as regeneration. Given thephysiological importance of synaptic processes and cell adhesionmechanisms in vivo, efforts are currently being under taken to identifynew, native proteins which are involved in synaptic machinery and celladhesion. Densin is further described in Kennedy, M. B, Trends Neurosci.(England), 20(6):264 (1997) and Apperson, et al., J. Neurosci.,16(21):6839 (1996).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as KIAA0231 and densin. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundproteins having leucine rich repeats. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of a novelpolypeptide which has homology to leucine rich repeat proteins,designated herein as PRO247.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Proteases are enzymatic proteins which are involved in a large number ofvery important biological processes in mammalian and non-mammalianorganisms. Numerous different protease enzymes from a variety ofdifferent mammalian and non-mammalian organisms have been bothidentified and characterized. The mammalian protease enzymes playimportant roles in many different biological processes including, forexample, protein digestion, activation, inactivation, or modulation ofpeptide hormone activity, and alteration of the physical properties ofproteins and enzymes.

In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industry andacademia to identify new, native protease homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. We herein describe the identification of novel polypeptideshaving homology to various protease enzymes, designated herein asPRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides.

41. PRO328

The GLIP protein family has been characterized as comprising zinc-fingerproteins which play important roles in embryogenesis. These proteins mayfunction as transcriptional regulatory proteins and are known to beamplified in a subset of human tumors. Glioma pathogenesis protein isstructurally related to a group of plant pathogenesis-related proteins.It is highly expressed in glioblastoma. See US Pat. Nos. 5,582,981(issued Dec. 10, 1996) and 5,322,801 (issued June 21, 1996), Ellington,A.D. et al., Nature 346:818 (1990), Grindley, J. C. et al., Dev. Biol.,188(2):337 (1997), Marine, J. C. et al., Mech. Dev., 63(2):211 (1997),The CRISP or cysteine rich secretory protein family are a group ofproteins which are also structurally related to a group of plantpathogenesis proteins. [Schwidetzky, U., Biochem. J., 321:325 (1997),Pfisterer, P., Mol. Cell Biol., 16(11):6160 (1996), Kratzschmar, J.,Eur. J. Biochem., 236(3):827 (1996)]. We describe herein theidentification of a novel polypeptide which has homology to GLIP andCRISP, designated herein as PRO328 polypeptides.

42. PRO335, PRO331 and PRO326

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein—protein interactions,protein—protein interactions can be more easily manipulated to regulatethe particular result of the protein—protein interaction. Thus, theunderlying mechanisms of protein—protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein—protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndrome,Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats and Ruoslahti,E. I., et al., WO9110727-A by La Jolla Cancer Research Foundationreporting that decorin binding to transforming growth factorβ hasinvolvement in a treatment for cancer, wound healing and scarring.Related by function to this group of proteins is the insulin like growthfactor (IGF), in that it is useful in wound-healing and associatedtherapies concerned with re-growth of tissue, such as connective tissue,skin and bone; in promoting body growth in humans and animals; and instimulating other growth-related processes. The acid labile subunit ofIGF (ALS) is also of interest in that it increases the half-life of IGFand is part of the IGF complex in vivo.

Another protein which has been reported to have leucine-rich repeats isthe SLIT protein which has been reported to be useful in treatingneuro-degenerative diseases such as Alzheimer's disease, nerve damagesuch as in Parkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-Al by YaleUniversity. Of particular interest is LIG-1, a membrane glycoproteinthat is expressed specifically in glial cells in the mouse brain, andhas leucine rich repeats and immunoglobulin-like domains. Suzuki, etal., J. Biol. Chem. (U.S.), 271(37):22522 (1996). Other studiesreporting on the biological functions of proteins having leucine richrepeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland),125(1-2):65-70 (December 1996) (gonadotropin receptor involvement);Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996)(apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein—protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as LIG-1, ALS and decorin. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundproteins having leucine rich repeats. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine rich repeatsuperfamily, designated herein as PRO335, PRO331 and PRO326polypeptides.

43. PRO332

Secreted proteins comprising a repeat characterized by an arrangement ofconserved leucine residues (leucine-rich repeat motif) have diversebiological roles. Certain proteoglycans, such as biglycan, fibromodulinand decorin, are, for example, characterized by the presence of aleucine-rich repeat of about 24 amino acids [Ruoslahti, Ann. Rev. Cell.Biol. 4229-255 (1988); Oldberg et al., EMBO J. 8, 2601-2604 (1989)]. Ingeneral, proteoglycans are believed to play a role in regulatingextracellular matrix, cartilage or bone function. The proteoglycandecorin binds to collagen type I and II and affects the rate of fibrilformation. Fibromodulin also binds collagen and delays fibril formation.Both fibromodulin and decorin inhibit the activity of transforminggrowth factor beta (TGF-β) (U.S. Pat. No. 5,583,103 issued Dec. 10,1996). TGF-β is known to play a key role in the induction ofextracellular matrix and has been implicated in the development offibrotic diseases, such as cancer and glomerulonephritis. Accordingly,proteoglycans have been proposed for the treatment of fibrotic cancer,based upon their ability to inhibit TGF-β's growth stimulating activityon the cancer cell. Proteoglycans have also been described aspotentially useful in the treatment of other proliferative pathologies,including rheumatoid arthritis, arteriosclerosis, adult respiratorydistress syndrome, cirrhosis of the liver, fibrosis of the lungs,post-myocardial infarction, cardiac fibrosis, post-angioplastyrestenosis, renal interstitial fibrosis and certain dermal fibroticconditions, such as keloids and scarring, which might result from burninjuries, other invasive skin injuries, or cosmetic or reconstructivesurgery (U.S. Pat. No. 5,654,270, issued Aug. 5, 1997).

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine rich repeatsuperfamily, designated herein as PRO332 polypeptides.

44. PRO334

Microfibril bundles and proteins found in association with thesebundles, particularly attachment molecules, are of interest in the fieldof dermatology, particularly in the study of skin which has been damagedfrom aging, injuries or the sun. Fibrillin microfibrils define thecontinuous elastic network of skin, and are present in dermis asmicrofibril bundles devoid of measurable elastin extending from thedermal-epithelial junction and as components of the thick elastic fiberspresent in the deep reticular dermis. Moreover, Marfan syndrome has beenlinked to mutations which interfere with multimerization of fibrillinmonomers or other connective tissue elements.

Fibulin-1 is a modular glycoprotein with amino-terminalanaphlatoxin-like modules followed by nine epidermal growth factor(EGF)-like modules and, depending on alternative splicing, four possiblecarboxyl termini. Fibulin-2 is a novel extracellular matrix proteinfrequently found in close association with microfibrils containingeither fibronectin or fibrillin. Thus, fibrillin, fibulin, and moleculesrelated thereto are of interest, particularly for the use of preventingskin from being damaged from aging, injuries or the sun, or forrestoring skin damaged from same. Moreover, these molecules aregenerally of interest in the study of connective tissue and attachmentmolecules and related mechanisms. Fibrillin, fibulin and relatedmolecules are further described in Adams, et al., J. Mol. Biol.,272(2):22636 (1997); Kielty and Shuttleworth, Microsc. Res. Tech.,38(4):413-27.(1997); and Child, J. Card. Surg. 12(2Supp.):131-5 (1997).

Currently, efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly secreted proteins which have homology to fibulin andfibrillin. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fibulin and fibrillin, designated hereinas PRO334 polypeptides.

45. PRO346

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment. Oneparticular method involves the creation of tumor or cancer specificmonoclonal antibodies (mAbs) which are specific to tumor antigens. SuchmAbs, which can distinguish between normal and cancerous cells areuseful in the diagnosis, prognosis and treatment of the disease.Particular antigens are known to be associated with neoplastic diseases,such as colorectal and breast cancer. Since colon cancer is a widespreaddisease, early diagnosis and treatment is an important medical goal.Diagnosis and treatment of cancer can be implemented using monoclonalantibodies (mAbs) specific therefore having fluorescent, nuclearmagnetic or radioactive tags. Radioactive genes, toxins and/or drugtagged mAbs can be used for treatment in situ with minimal patientdescription.

Carcinoembryonic antigen (CEA) is a glycoprotein found in human coloncancer and the digestive organs of a 2-6 month human embryos. CEA is aknown human tumor marker and is widely used in the diagnosis ofneoplastic diseases, such as colon cancer. For example, when the serumlevels of CEA are elevated in a patient, a drop of CEA levels aftersurgery would indicate the tumor resection was successful. On the otherhand, a subsequent rise in serum CEA levels after surgery would indicatethat metastases of the original tumor may have formed or that newprimary tumors may have appeared. CEA may also be a target for mAb,antisense nucleotides

46. PRO268

Protein disulfide isomerase is an enzymatic protein which is involved inthe promotion of correct refolding of proteins through the establishmentof correct disulfide bond formation. Protein disulfide isomerase wasinitially identified based upon its ability to catalyze the renaturationof reduced denatured RNAse (Goldberger et al., J. Biol. Chem.239:1406-1410(1964) and Epstein et al., Cold Spring Harbor Symp. Quant.Biol. 28:439-449 (1963)). Protein disulfide isomerase has been shown tobe a resident enzyme of the endoplasmic reticulum which is retained inthe endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence atits C-terminus.

Given the importance of disulfide bond-forming enzymes and theirpotential uses in a number of different applications, for example inincreasing the yield of correct refolding of recombinantly producedproteins, efforts are currently being undertaken by both industry andacademia to identify new, native proteins having homology to proteindisulfide isomerase. Many of these efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel protein disulfide isomerase homologs. We herein describe anovel polypeptide having homology to protein disulfide isomerase,designated herein as PRO268.

47. PRO330

Prolyl 4-hydroxylase is an enzyme which functions topost-translationally hydroxylate proline residues at the Y position ofthe amino acid sequence Gly-X-Y, which is a repeating three amino acidsequence found in both collagen and procollagen. Hydroxylation ofproline residues at the Y position of the Gly-X-Y amino acid triplet toform 4-hydroxyproline residues at those positions is required beforenewly synthesized collagen polypeptide chains may fold into their properthree-dimensional triple-helical conformation. If hydroxylation does notoccur, synthesized collagen polypeptides remain non-helical, are poorlysecreted by cells and cannot assemble into stable functional collagenfibrils. Vuorio et al., Proc. Natl. Acad. Sci. USA 89:7467-7470 (1992).Prolyl 4 hydroxylase is comprised of at least two different polypeptidesubunits, alpha and beta.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins. Many effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. Based uponthese efforts, Applicants have herein identified and describe a novelpolypeptide having homology to the alpha subunit of prolyl4-hydroxylase, designated herein as PRO330.

48. PRO339 and PRO310

Fringe is a protein which specifically blocks serrate-mediatedactivation of notch in the dorsal compartment of the Drosophila wingimaginal disc. Fleming, et al., Development, 124(15):2973-81 (1997).Therefore, fringe is of interest for both its role in development aswell as its ability to regulate serrate, particularly serrate'ssignaling abilities. Also of interest are novel polypeptides which mayhave a role in development and/or the regulation of serrate-likemolecules. Of particular interest are novel polypeptides having homologyto fringe as identified and described herein, designated herein asPRO339 and PRO310 polypeptides.

49. PRO244

Lectins are a class of proteins comprising a region that bindscarbohydrates specifically and non-covalently. Numerous lectins havebeen identified in higher animals, both membrane-bound and soluble, andhave been implicated in a variety of cell-recognition phenomena andtumor metastasis.

Most lectins can be classified as either C-type (calcium-dependent) orS-type (thiol-dependent).

Lectins are thought to play a role in regulating cellular events thatare initiated at the level of the plasma membrane. For example, plasmamembrane associated molecules are involved in the activation of varioussubsets of lymphoid cells, e.g. T-lymphocytes, and it is known that cellsurface molecules are responsible for activation of these cells andconsequently their response during an immune reaction.

A particular group of cell adhesion molecules, selecting, belong in thesuperfamily of C-type lectins. This group includes L-selectin(peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1,gp90^(MEL), gp100^(MEL), gp110^(MEL), MEL-14 antigen, Leu-8 antigen,TQ-1 antigen, DREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1),and P-selectin (LEC-CAM-3, LECAM-3, GMP-140, PADGEM). The structure ofselectins consists of a C-type lectin (carbohydrate binding) domain, anepidermal growth factor-like (EGF-like) motif, and variable numbers ofcomplement regulatory (CR) motifs. Selectins are associated withleukocyte adhesion, e.g. the attachment of neutrophils to venularendothelial cells adjacent to inflammation (E-selectin), or with thetrafficking of lymphocytes from blood to secondary lymphoid organs, e.g.lymph nodes and Peyer's patches (L-selectin).

Another exemplary lectin is the cell-associated macrophage antigen,Mac-2 that is believed to be involved in cell adhesion and immuneresponses. Macrophages also express a lectin that recognizes Tn Ag, ahuman carcinoma-associated epitope.

Another C-type lectin is CD95 (Fas antigen/APO-1) that is an importantmediator of immunologically relevant regulated or programmed cell death(apoptosis). “Apoptosis” is a non-necrotic cell death that takes placein metazoan animal cells following activation of an intrinsic cellsuicide program. The cloning of Fas antigen is described in PCTpublication WO 91/10448, and European patent application EP510691. Themature Fas molecule consists of 319 amino acids of which 157 areextracellular, 17 constitute the transmembrane domain, and 145 areintracellular. Increased levels of Fas expression at T cell surface havebeen associated with tumor cells and HIV-infected cells. Ligation ofCD95 triggers apoptosis in the presence of interleukin-1 (IL-2).

C-type lectins also include receptors for oxidized low-densitylipoprotein (LDL). This suggests a possible role in the pathogenesis ofatherosclerosis.

We herein describe the identification and characterization of novelpolypeptides having homology to C-type lectins, designated herein asPRO244 polypeptides.

SUMMARY OF THE INVENTION

1. PRO211 and PRO217

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to EGF, designated in the present application as “PRO211” and “PRO217” polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO211 or PRO217 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding EGF-likehomologue PRO211 and PRO217 polypeptides of FIG. 2 (SEQ ID NO:2) and/or4 (SEQ ID NO:4) indicated in FIG. 1 (SEQ ID NO1) and/or FIG. 3 (SEQ IDNO:3), respectively, or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO211 and PRO217EGF-like homologue PRO211 and PRO217 polypeptides. In particular, theinvention provides isolated native sequence PRO211 and PRO217 EGF-likehomologue polypeptides, which in one embodiment, includes an amino acidsequence comprising residues: 1 to 353 of FIG. 2 (SEQ ID NO:2) or (2) 1to 379 of FIG. 4 (SEQ ID NO: 4).

2. PRO230

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO230”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO230 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO230 polypeptidehaving amino acid residues 1 through 467 of FIG. 6 (SEQ ID NO:12), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO230polypeptide. In particular, the invention provides isolated nativesequence PRO230 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 through 467 of FIG. 6 (SEQ IDNO:12).

In another embodiment, the invention provides an expressed sequence tag(EST) comprising the nucleotide sequence of SEQ ID NO:13 (FIG. 7) whichis herein designated as DNA20088.

3. PRO232

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO232”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO232 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO232 polypeptidehaving amino acid residues 1 to 114 of FIG. 9 (SEQ ID NO:18), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO232polypeptide. In particular, the invention provides isolated nativesequence PRO232 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 114 of FIG. 9 (SEQ ID NO:18).

4. PRO187

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO187”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO187 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO187 polypeptideof FIG. 11 (SEQ ID NO:23), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid comprising the coding sequence of FIG.10 (SEQ ID NO:22) or its complement. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA27864-1155, deposited with the ATCC under accession number ATCC209375, alternatively the coding sequence of clone DNA27864-1155,deposited under accession number ATCC 209375.

In yet another embodiment, the invention provides isolated PRO187polypeptide. In particular, the invention provides isolated nativesequence PRO187 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 205 of FIG. 11 (SEQ ID NO:23).Alternatively, the invention provides a polypeptide encoded by thenucleic acid deposited under accession number ATCC 209375.

5. PRO265

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO265”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO265 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO265 polypeptidehaving amino acid residues 1 to 660 of FIG. 13 (SEQ ID NO:28), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO265polypeptide. In particular, the invention provides isolated nativesequence PRO265 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 660 of FIG. 13 (SEQ ID NO:28). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO265 polypeptide.

6. PRO219

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO219”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO219 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO219 polypeptidehaving amino acid residues 1 to 915 of FIG. 15 (SEQ ID NO:34), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO219polypeptide. In particular, the invention provides isolated nativesequence PRO219 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 915 of FIG. 15 (SEQ ID NO:34).

7. PRO246

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO246”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO246 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO246 polypeptidehaving amino acid residues 1 to 390 of FIG. 17 (SEQ ID NO:39), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO246polypeptide. In particular, the invention provides isolated nativesequence PRO246 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 390 of FIG. 17 (SEQ ID NO:39). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO246 polypeptide.

8. PRO228

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CD97, EMR1 and latrophilin, wherein the polypeptideis designated in the present application as “PRO228”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO228 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO228 polypeptidehaving amino acid residues 1 to 690 of FIG. 19 (SEQ ID NO:49), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO228polypeptide. In particular, the invention provides isolated nativesequence PRO228 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 690 of FIG. 19 (SEQ ID NO:49). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO228 polypeptide.

In another embodiment, the invention provides an expressed sequence tag(EST) comprising the nucleotide sequence of SEQ ID NO:50, designatedherein as DNA21951.

9. PRO533

Applicants have identified a cDNA clone (DNA49435-1219) that encodes anovel polypeptide, designated in the present application as PRO533.

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO533 polypeptide comprising the sequence of aminoacids 23 to 216 of FIG. 22 (SEQ ID NO:59), or (b) the complement of theDNA molecule of (a). The sequence identity preferably is about 85%, morepreferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 23 to 216 of FIG. 22 (SEQ ID NO:59). Preferably, the highestdegree of sequence identity occurs within the secreted portion (aminoacids 23 to 216 of FIG. 22, SEQ ID NO:59). In a further embodiment, theisolated nucleic acid molecule comprises DNA encoding a PRO533polypeptide having amino acid residues 1 to 216 of FIG. 22 (SEQ IDNO:59), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA49435-1219, deposited with the ATCC under accession number ATCC209480.

In yet another embodiment, the invention provides isolated PRO533polypeptide. In particular, the invention provides isolated nativesequence PRO533 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 23 to 216 of FIG. 22 (SEQ ID NO:59).Native PRO533 polypeptides with or without the native signal sequence(amino acids 1 to 22 in FIG. 22 (SEQ ID NO:59)), and with or without theinitiating methionine are specifically included. Alternatively, theinvention provides a PRO533 polypeptide encoded by the nucleic aciddeposited under accession number ATCC 209480.

10. PRO245

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO245”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO245 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO245 polypeptidehaving amino acid residues 1 to 312 of FIG. 24 (SEQ ID NO:64), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO245polypeptide. In particular, the invention provides isolated nativesequence PRO245 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues I to 312 of FIG. 24 (SEQ ID NO:64).

11. PRO220, PRO221 and PRO227

Applicants have identified cDNA clones that each encode novelpolypeptides, all having leucine rich repeats. These polypeptides aredesignated in the present application as PRO220, PRO221 and PRO227.

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA respectively encoding PRO220, PRO221 andPRO227, respectively. In one aspect, provided herein is an isolatednucleic acid comprises DNA encoding the PRO220 polypeptide having aminoacid residues 1 through 708 of FIG. 26 (SEQ ID NO:69), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. Also provided herein is an isolated nucleic acidcomprises DNA encoding the PRO221 polypeptide having amino acid residues1 through 259 of FIG. 28 (SEQ ID NO:71), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.Moreover, also provided herein is an isolated nucleic acid comprises DNAencoding the PRO227 polypeptide having amino acid residues 1 through 620of FIG. 30 (SEQ ID NO:73), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO220, PRO221and PRO227 polypeptides. In particular, provided herein is the isolatednative sequence for the PRO220 polypeptide, which in one embodiment,includes an amino acid sequence comprising residues 1 to 708 of FIG. 26(SEQ ID NO:69). Additionally provided herein is the isolated nativesequence for the PRO221 polypeptide, which in one embodiment, includesan amino acid sequence comprising residues 1 to 259 of FIG. 28 (SEQ IDNO:71). Moreover, provided herein is the isolated native sequence forthe PRO227 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 620 of FIG. 30 (SEQ ID NO:73).

12. PRO258

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CRTAM and poliovirus receptor precursors, wherein thepolypeptide is designated in the present application as “PRO258”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO258 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO258 polypeptidehaving amino acid residues 1 to 398 of FIG. 32 (SEQ ID NO:84), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO258polypeptide. In particular, the invention provides isolated nativesequence PRO258 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 398 of FIG. 32 (SEQ ID NO:84). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO258 polypeptide.

13. PRO266

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO266”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO266 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO266 polypeptidehaving amino acid residues 1 to 696 of FIG. 34 (SEQ ID NO:91), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO266polypeptide. In particular, the invention provides isolated nativesequence PRO266 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 696 of FIG. 34 (SEQ ID NO:91).

14. PRO269

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as PRO269.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO269 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO269 polypeptidehaving amino acid residues 1 to 490 of FIG. 36 (SEQ ID NO:96), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO269polypeptide. In particular, the invention provides isolated nativesequence PRO269 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 490 of FIG. 36 (SEQ ID NO:96). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO269 polypeptide.

15. PRO287

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO287”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO287 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO287 polypeptidehaving amino acid residues 1 to 415 of FIG. 38 (SEQ ID NO:104), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO287polypeptide. In particular, the invention provides isolated nativesequence PRO287 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 415 of FIG. 38 (SEQ ID NO:104).

16. PRO214

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO214”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO214 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO214 polypeptideof FIG. 40 (SEQ ID NO:109), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid comprising the coding sequence of FIG.39 (SEQ ID NO:108) or its complement. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA32286-1191, deposited with ATCC under accession number ATCC 209385.

In yet another embodiment, the invention provides isolated PRO214polypeptide. In particular, the invention provides isolated nativesequence PRO214 polypeptide, which in one embodiment, includes an aminoacid sequence comprising the residues of FIG. 40 (SEQ ID NO:109).Alternatively, the invention provides a polypeptide encoded by thenucleic acid deposited under accession number ATCC 209385.

17. PRO317

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO317”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO317 polypeptide. In one aspect, theisolated nucleic acid comprises DNA (SEQ ID NO:113) encoding PRO317polypeptide having amino acid residues 1 to 366 of FIG. 42, or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO317polypeptide. In particular, the invention provides isolatednative-sequence PRO317 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 366 of FIG. 42 (SEQ IDNO:114).

In yet another embodiment, the invention supplies a method of detectingthe presence of PRO317 in a sample, the method comprising:

a) contacting a detectable anti-PRO317 antibody with a sample suspectedof containing PRO317; and

b) detecting binding of the antibody to the sample; wherein the sampleis selected from the group consisting of a body fluid, a tissue sample,a cell extract, and a cell culture medium.

In a still further embodiment a method is provided for determining thepresence of PRO317 mRNA in a sample, the method comprising:

a) contacting a sample suspected of containing PRO317 mRNA with adetectable nucleic acid probe that hybridizes under moderate tostringent conditions to PRO317 mRNA; and

b) detecting hybridization of the probe to the sample.

Preferably, in this method the sample is a tissue sample and thedetecting step is by in situ hybridization, or the sample is a cellextract and detection is by Northern analysis.

Further, the invention provides a method for treating aPRO317-associated disorder comprising administering to a mammal aneffective amount of the PRO317 polypeptide or a composition thereofcontaining a carrier, or with an effective amount of a PRO317 agonist orPRO317 antagonist, such as an antibody which binds specifically toPRO317.

18. PRO301

Applicants have identified a cDNA clone (DNA40628-1216) that encodes anovel polypeptide, designated in the present application as “PRO301”.

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO301 polypeptide comprising the sequence of aminoacids 28 to 258 of FIG. 44 (SEQ ID NO:119), or (b) the complement of theDNA molecule of (a). The sequence identity preferably is about 85%, morepreferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 28 to 258 of FIG. 44 (SEQ ID NO:119). Preferably, the highestdegree of sequence identity occurs within the extracellular domains(amino acids 28 to 258 of FIG. 44, SEQ ID NO:119). In a furtherembodiment, the isolated nucleic acid molecule comprises DNA encoding aPRO301 polypeptide having amino acid residues 28 to 299 of FIG. 44 (SEQID NO:119), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA40628-1216, deposited with the ATCC under accession number ATCC209432, alternatively the coding sequence of clone DNA40628-1216,deposited under accession number ATCC 209432.

In yet another embodiment, the invention provides isolated PRO301polypeptide. In particular, the invention provides isolated nativesequence PRO301 polypeptide, which in one embodiment, includes an aminoacid sequence comprising the extracellular domain residues 28 to 258 ofFIG. 44 (SEQ ID NO:119). Native PRO301 polypeptides with or without thenative signal sequence (amino acids 1 to 27 in FIG. 44 (SEQ ID NO:119),and with or without the initiating methionine are specifically included.Additionally, the sequences of the invention may also comprise thetransmembrane domain (residues 236 to about 258 in FIG. 44; SEQ IDNO:119) and/or the intracellular domain (about residue 259 to 299 inFIG. 44; SEQ ID NO:119). Alternatively, the invention provides a PRO301polypeptide encoded by the nucleic acid deposited under accession numberATCC 209432.

19. PRO224

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO224”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO224 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO224 polypeptidehaving amino acid residues 1 to 282 of FIG. 46 (SEQ ID NO:127), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO224polypeptide. In particular, the invention provides isolated nativesequence PRO224 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 282 of FIG. 46 (SEQ ID NO:127).

20. PRO222

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO222”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO222 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO222 polypeptidehaving amino acid residues 1 to 490 of FIG. 48 (SEQ ID NO:132), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO222polypeptide. In particular, the invention provides isolated nativesequence PRO222 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 490 of FIG. 48 (SEQ ID NO:132).

21. PRO234

Applicants have identified a cDNA clone that encodes a novel lectinpolypeptide molecule, designated in the present application as “PRO234”.

In one embodiment, the invention provides an isolated nucleic acidencoding a novel lectin comprising DNA encoding a PRO234 polypeptide. Inone aspect, the isolated nucleic acid comprises the DNA encoding PRO234polypeptides having amino acid residues 1 to 382 of FIG. 50 (SEQ IDNO:137), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides an isolated nucleic acid molecule comprising the nucleotidesequence of FIG. 49 (SEQ ID NO:136).

In another embodiment, the invention provides isolated novel PRO234polypeptides. In particular, the invention provides isolated nativesequence PRO234 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 382 of FIG. 50 (SEQ ID NO:137).

In yet another embodiment, the invention provides oligonucleotide probesuseful for isolating genomic and cDNA nucleotide sequences.

22. PRO231

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to a putative acid phosphatase, wherein the polypeptideis designated in the present application as “PRO231”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO231 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO231 polypeptidehaving amino acid residues 1 to 428 of FIG. 52 (SEQ ID NO:142), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO231polypeptide. In particular, the invention provides isolated nativesequence PRO231 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 428 of FIG. 52 (SEQ ID NO:142).

23. PRO229

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to scavenger receptors wherein the polypeptide isdesignated in the present application as “PRO229”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO229 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO229 polypeptidehaving amino acid residues 1 to 347 of FIG. 54 (SEQ ID NO:148), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO229polypeptide. In particular, the invention provides isolated nativesequence PRO229 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 347 of FIG. 54 (SEQ ID NO:148).

24. PRO238

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to reductase, wherein the polypeptide is designated inthe present application as “PRO238”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO238 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO238 polypeptidehaving amino acid-residues 1 to 310 of FIG. 56 (SEQ ID NO:153), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO238polypeptide. In particular, the invention provides isolated nativesequence PRO238 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 310 of FIG. 56 (SEQ ID NO:153).

25. PRO233

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO233”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO233 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO233 polypeptidehaving amino acid residues 1 to 300 of FIG. 58 (SEQ ID NO:159), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO233polypeptide. In particular, the invention provides isolated nativesequence PRO233 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 300 of FIG. 58 (SEQ ID NO:159).

26. PRO223

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to serine carboxypeptidase polypeptides, wherein thepolypeptide is designated in the present application as “PRO223”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO223 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO223 polypeptidehaving amino acid residues 1 to 476 of FIG. 60 (SEQ ID NO:164), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO223polypeptide. In particular, the invention provides isolated nativesequence PRO223 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 476 of FIG. 60 (SEQ ID NO:164).

27. PRO235

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO235”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO235 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO235 polypeptidehaving amino acid residues 1 to 552 of FIG. 62 (SEQ ID NO:170), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO235polypeptide. In particular, the invention provides isolated nativesequence PRO235 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 552 of FIG. 62 (SEQ ID NO:170).

28. PRO236 and PRO262

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to β-galactosidase, wherein those polypeptides aredesignated in the present application as “PRO236” and “PRO262”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO236 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO236 polypeptidehaving amino acid residues 1 to 636 of FIG. 64 (SEQ ID NO:175), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO262 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO262 polypeptidehaving amino acid residues 1 to 654 of FIG. 66 (SEQ ID NO:177), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO236polypeptide. In particular, the invention provides isolated nativesequence PRO236 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 636 of FIG. 64 (SEQ ID NO:175).

In another embodiment, the invention provides isolated PRO262polypeptide. In particular, the invention provides isolated nativesequence PRO262 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 654 of FIG. 66 (SEQ ID NO:177).

29. PRO239

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO239”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO239 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO239 polypeptidehaving amino acid residues 1 to 501 of FIG. 68 (SEQ ID NO:185), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO239polypeptide. In particular, the invention provides isolated nativesequence PRO239 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 501 of FIG. 68 (SEQ ID NO:185).

30. PRO257

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO257”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO257 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO257 polypeptidehaving amino acid residues 1 to 607 of FIG. 70 (SEQ ID NO:190), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO257polypeptide. In particular, the invention provides isolated nativesequence PRO257 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 607 of FIG. 70 (SEQ ID NO:190).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO257 polypeptide.

31. PRO260

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO260”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO260 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO260 polypeptidehaving amino acid residues 1 to 467 of FIG. 72 (SEQ ID NO:195), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO260polypeptide. In particular, the invention provides isolated nativesequence PRO260 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 467 of FIG. 72 (SEQ ID NO:195).

32. PRO263

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CD44 antigen, wherein the polypeptide is designatedin the present application as “PRO263”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO263 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO263 polypeptidehaving amino acid residues 1 to 322 of FIG. 74 (SEQ ID NO:201), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO263polypeptide. In particular, the invention provides isolated nativesequence PRO263 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 322 of FIG. 74 (SEQ ID NO:201).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO263 polypeptide.

33. PRO270

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO270”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO270 polypeptide. In one aspect,the isolated nucleic acid comprises DNA which includes the sequenceencoding the PRO270 polypeptide having amino acid residues 1 to 296 ofFIG. 76 (SEQ ID NO:207), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO270polypeptide. In particular, the invention provides isolated nativesequence PRO270 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 296 of FIG. 76 (SEQ ID NO:207).

34. PRO271

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to the proteoglycan link protein, wherein thepolypeptide is designated in the present application as “PRO271”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO271 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO271 polypeptidehaving amino acid residues 1 to 360 of FIG. 78 (SEQ ID NO:213), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO271polypeptide. In particular, the invention provides isolated nativesequence PRO271 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 360 of FIG. 78 (SEQ ID NO:213).

35. PRO272

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO272”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO272 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO272 polypeptidehaving amino acid residues 1 to 328 of FIG. 80 (SEQ ID NO:221), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO272polypeptide. In particular, the invention provides isolated nativesequence PRO272 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 328 of FIG. 80 (SEQ ID NO:211).

36. PRO294

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO294”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO294 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO294 polypeptidehaving amino acid residues 1 to 550 of FIG. 82 (SEQ ID NO:227), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO294polypeptide. In particular, the invention provides isolated nativesequence PRO294 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 550 of FIG. 82 (SEQ ID NO:227).

37. PRO295

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO295”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO295 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO295 polypeptidehaving amino acid residues 1 to 350 of FIG. 84 (SEQ ID NO:236), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO295polypeptide. In particular, the invention provides isolated nativesequence PRO295 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 350 of FIG. 84 (SEQ ID NO:236).

38. PRO293

Applicants have identified a cDNA clone that encodes a novel humanneuronal leucine rich repeat polypeptide, wherein the polypeptide isdesignated in the present application as “PRO293”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO293 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO293 polypeptidehaving amino acid residues 1 to 713 of FIG. 86 (SEQ ID NO:245), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO293polypeptide. In particular, the invention provides isolated nativesequence PRO293 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 713 of FIG. 86 (SEQ ID NO:245).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO293 polypeptide.

39. PRO247

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving leucine rich repeats wherein the polypeptide is designated in thepresent application as “PRO247”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO247 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO247 polypeptidehaving amino acid residues 1 to 546 of FIG. 88 (SEQ ID NO:250), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO247polypeptide. In particular, the invention provides isolated nativesequence PRO247 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 546 of FIG. 88 (SEQ ID NO:250).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO247 polypeptide.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to various proteases, wherein those polypeptide aredesignated in the present application as “PRO302”, “PRO303”, “PRO304”,“PRO307” and “PRO343” polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO302 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO302 polypeptidehaving amino acid residues 1 to 452 of FIG. 90 (SEQ ID NO:255), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO303 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO303 polypeptidehaving amino acid residues 1 to 314 of FIG. 92 (SEQ ID NO:257), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In yet another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO304 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO304polypeptide having amino acid residues 1 to 556 of FIG. 94 (SEQ IDNO:259), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO307 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO307 polypeptidehaving amino acid residues 1 to 383 of FIG. 96 (SEQ ID NO:261), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO343 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO343 polypeptidehaving amino acid residues 1 to 317 of FIG. 98 (SEQ ID NO:263), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO302polypeptide. In particular, the invention provides isolated nativesequence PRO302 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 452 of FIG. 90 (SEQ ID NO:255).

In another embodiment, the invention provides isolated PRO303polypeptide. In particular, the invention provides isolated nativesequence PRO303 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 314 of FIG. 92 (SEQ ID NO:257).

In another embodiment, the invention provides isolated PRO304polypeptide. In particular, the invention provides isolated nativesequence PRO304 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 556 of FIG. 94 (SEQ ID NO:259).

In another embodiment, the invention provides isolated PRO307polypeptide. In particular, the invention provides isolated nativesequence PRO307 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 383 of FIG. 96 (SEQ ID NO:261).

In another embodiment, the invention provides isolated PRO343polypeptide. In particular, the invention provides isolated nativesequence PRO343 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 317 of FIG. 98 (SEQ ID NO:263).

41. PRO328

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO328”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO328 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO328 polypeptidehaving amino acid residues 1 to 463 of FIG. 100 (SEQ ID NO:285), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO328polypeptide. In particular, the invention provides isolated nativesequence PRO328 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 463 of FIG. 100 (SEQ ID NO:285).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO306 polypeptide.

42. PRO335, PRO331 and PRO326

Applicants have identified three cDNA clones that respectively encodethree novel polypeptides, each having leucine rich repeats and homologyto LIG-1 and ALS. These polypeptides are designated in the presentapplication as PRO335, PRO331 and PRO326, respectively.

In one embodiment, the invention provides three isolated nucleic acidmolecules comprising DNA respectively encoding PRO335, PRO331 andPRO326, respectively. In one aspect, herein is provided an isolatednucleic acid comprising DNA encoding the PRO335 polypeptide having aminoacid residues 1 through 1059 of FIG. 102 (SEQ ID NO:290), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. Also provided herein is an isolated nucleic acidcomprises DNA encoding the PRO331 polypeptide having amino acid residues1 through 640 of FIG. 104 (SEQ ID NO:292), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.Additionally provided herein is an isolated nucleic acid comprises DNAencoding the PRO326 polypeptide having amino acid residues 1 through1119 of FIG. 106 (SEQ ID NO:294), or is complementary to such encodingnucleic acid sequence, and remains stably bound to it under at leastmoderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO335, PRO331and PRO326 polypeptides or extracellular domains thereof. In particular,the invention provides isolated native sequence for the PRO335polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 1059 of FIG. 102 (SEQ ID NO:290). Alsoprovided herein is the isolated native sequence for the PRO331polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 640 of FIG. 104 (SEQ ID NO:292). Alsoprovided herein is the isolated native sequence for the PRO326polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 1119 of FIG. 106 (SEQ ID NO:294).

43. PRO332

Applicants have identified a cDNA clone (DNA40982-1235) that encodes anovel polypeptide, designated in the present application as “PRO332.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity to(a) a DNA molecule encoding a PRO358 polypeptide comprising the sequenceof amino acids 49 to 642 of FIG. 108 (SEQ ID NO:310), or (b) thecomplement of the DNA molecule of (a). The sequence identity preferablyis about 85%, more preferably about 90%, most preferably about 95%. Inone aspect, the isolated nucleic acid has at least about 80%, preferablyat least about 85%, more preferably at least about 90%, and mostpreferably at least about 95% sequence identity with a polypeptidehaving amino acid residues 1 to 642 of FIG. 108 (SEQ ID NO:310).Preferably, the highest degree of sequence identity occurs within theleucine-rich repeat domains (amino acids 116 to 624 of FIG. 108, SEQ IDNO:310). In a further embodiment, the isolated nucleic acid moleculecomprises DNA encoding a PRO332 polypeptide having amino acid residues49 to 642 of FIG. 108 (SEQ ID NO:310), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO332polypeptides. In particular, the invention provides isolated nativesequence PRO332 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 49 to 624 of FIG. 108 (SEQ ID NO:310).Native PRO332 polypeptides with or without the native signal sequence(amino acids 1 to 48 in FIG. 108, SEQ ID NO:310), and with or withoutthe initiating methionine are specifically included.

44. PRO334

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to fibulin and fibrillin, wherein the polypeptide isdesignated in the present application as “PRO334”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO334 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO334 polypeptidehaving amino acid residues 1 to 509 of FIG. 110 (SEQ ID NO:315), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO334polypeptide. In particular, the invention provides isolated nativesequence PRO334 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 509 of FIG. 110 (SEQ ID NO:315).

45. PRO346

Applicants have identified a cDNA clone (DNA44167-1243) that encodes anovel polypeptide, designated in the present application as “PRO346.”

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO346 polypeptide comprising the sequence of aminoacids 19 to 339 of FIG. 112 (SEQ ID NO:320), or (b) the complement ofthe DNA molecule of (a). The sequence identity preferably is about 85%,more preferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 19 to 339 of FIG. 112 (SEQ ID NO:320). Preferably, the highestdegree of sequence identity occurs within the extracellular domains(amino acids 19 to 339 of FIG. 112, SEQ ID NO:320). In alternativeembodiments, the polypeptide by which the homology is measured comprisesthe residues 1-339, 19-360 or 19-450 of FIG. 112, SEQ ID NO:320). In afurther embodiment, the isolated nucleic acid molecule comprises DNAencoding a PRO346 polypeptide having amino acid residues 19 to 339 ofFIG. 112 (SEQ ID NO:320), alternatively residues 1-339, 19-360 or 19-450of FIG. 112 (SEQ ID NO:320) or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid of the full length protein of cloneDNA44167-1243, deposited with the ATCC under accession number ATCC209434, alternatively the coding sequence of clone DNA44167-1243,deposited under accession number ATCC 209434.

In yet another embodiment, the invention provides isolated PRO346polypeptide. In particular, the invention provides isolated nativesequence PRO346 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 19 to 339 of FIG. 112 (SEQ ID NO:320).Native PRO346 polypeptides with or without the native signal sequence(residues 1 to 18 in FIG. 112 (SEQ ID NO:320), with or without theinitiating methionine, with or without the transmembrane domain(residues 340 to 360) and with or without the intracellular domain(residues 361 to 450) are specifically included. Alternatively, theinvention provides a PRO346 polypeptide encoded by the nucleic aciddeposited under accession number ATCC 209434.

46. PRO268

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to protein disulfide isomerase, wherein the polypeptideis designated in the present application as “PRO268”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO268 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO268 polypeptidehaving amino acid residues 1 to 280 of FIG. 114 (SEQ ID NO:325), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO268polypeptide. In particular, the invention provides isolated nativesequence PRO268 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 280 of FIG. 114 (SEQ ID NO:325).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO268 polypeptide.

47. PRO330

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to the alpha subunit of prolyl 4-hydroxylase, whereinthe polypeptide is designated in the present application as “PRO330”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO330 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO330 polypeptidehaving amino acid residues 1 to 533 of FIG. 116 (SEQ ID NO:332), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO330polypeptide. In particular, the invention provides isolated nativesequence PRO330 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 533 of FIG. 116 (SEQ ID NO:332).

48. PRO339 and PRO310

Applicants have identified two cDNA clones wherein each clone encodes anovel polypeptide having homology to fringe, wherein the polypeptidesare designated in the present application as “PRO339” and “PRO310”.

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA encoding a PRO339 and/or a PRO310 polypeptide.In one aspect, the isolated nucleic acid comprises DNA encoding thePRO339 polypeptide having amino acid residues 1 to 772 of FIG. 118 (SEQID NO:339), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO310 polypeptide having aminoacid residues 1 to 318 of FIG. 120 (SEQ ID NO:341), or is complementaryto such encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO339 as well asisolated PRO310 polypeptides. In particular, the invention providesisolated native sequence PRO339 polypeptide, which in one embodiment,includes an amino acid sequence comprising residues 1 to 772 of FIG. 118(SEQ ID NO:339). The invention further provides isolated native sequencePRO310 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 318 of FIG. 120 (SEQ ID NO:341).

49. PRO244

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO244”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO244 polypeptide. In one aspect, theisolated nucleic acid comprises DNA encoding PRO244 polypeptide havingamino acid residues 1 to 219 of FIG. 122 (SEQ ID NO:377), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO244polypeptide. In particular, the invention provides isolated nativesequence PRO244 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 219 of FIG. 122 (SEQ ID NO:377).

50. Additional Embodiments

In other embodiments of the present invention, the invention providesvectors comprising DNA encoding any of the herein describedpolypeptides. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli, or yeast. Aprocess for producing any of the herein described polypeptides isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired polypeptide and recovering thedesired polypeptide from the cell culture.

In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein described polypeptidesfused to an epitope tag sequence or a Fc region of an immunoglobulin.

In another embodiment, the invention provides an antibody whichspecifically binds to any of the above or below described polypeptides.Optionally, the antibody is a monoclonal antibody, humanized antibody,antibody fragment or single-chain antibody.

In yet other embodiments, the invention provides oligonucleotide probesuseful for isolating genomic and cDNA nucleotide sequences, whereinthose probes may be derived from any of the above or below describednucleotide sequences.

In other embodiments, the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence that encodes a PROpolypeptide.

In one aspect, the isolated nucleic acid molecule comprises a nucleotidesequence having at least about 80% sequence identity, preferably atleast about 81% sequence identity, more preferably at least about 82%sequence identity, yet more preferably at least about 83% sequenceidentity, yet more preferably at least about 84% sequence identity, yetmore preferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet more preferably atleast about 87% sequence identity, yet more preferably at least about88% sequence identity, yet more preferably at least about 89% sequenceidentity, yet more preferably at least about 90% sequence identity, yetmore preferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet more preferably atleast about 93% sequence identity, yet more preferably at least about94% sequence identity, yet more preferably at least about 95% sequenceidentity, yet more preferably at least about 96% sequence identity, yetmore preferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet more preferablyat least about 99% sequence identity to (a) a DNA molecule encoding aPRO polypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein, or (b) the complementof the DNA molecule of (a).

In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% sequence identity,preferably at least about 81% sequence identity, more preferably atleast about 82% sequence identity, yet more preferably at least about83% sequence identity, yet more preferably at least about 84% sequenceidentity, yet more preferably at least about 85% sequence identity, yetmore preferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet more preferably atleast about 88% sequence identity, yet more preferably at least about89% sequence identity, yet more preferably at least about 90% sequenceidentity, yet more preferably at least about 91% sequence identity, yetmore preferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet more preferably atleast about 94% sequence identity, yet more preferably at least about95% sequence identity, yet more preferably at least about 96% sequenceidentity, yet more preferably at least about 97% sequence identity, yetmore preferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNA moleculecomprising the coding sequence of a full-length PRO polypeptide cDNA asdisclosed herein, the coding sequence of a PRO polypeptide lacking thesignal peptide as disclosed herein or the coding sequence of anextracellular domain of a transmembrane PRO polypeptide, with or withoutthe signal peptide, as disclosed herein, or (b) the complement of theDNA molecule of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising a nucleotide sequence having at least about 80%sequence identity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to (a) a DNAmolecule that encodes the same mature polypeptide encoded by any of thehuman protein cDNAs deposited with the ATCC as disclosed herein, or (b)the complement of the DNA molecule of (a).

Another aspect the invention provides an isolated nucleic acid moleculecomprising a nucleotide sequence encoding a PRO polypeptide which iseither transmembrane domain-deleted or transmembrane domain-inactivated,or is complementary to such encoding nucleotide sequence, wherein thetransmembrane domain(s) of such polypeptide are disclosed herein.Therefore, soluble extracellular domains of the herein described PROpolypeptides are contemplated.

Another embodiment is directed to fragments of a PRO polypeptide codingsequence, or the complement thereof, that may find use as, for example,hybridization probes or for encoding fragments of a PRO polypeptide thatmay optionally encode a polypeptide comprising a binding site for ananti-PRO antibody. Such nucleic acid fragments are usually at leastabout 20 nucleotides in length, preferably at least about 30 nucleotidesin length, more preferably at least about 40 nucleotides in length, yetmore preferably at least about 50 nucleotides in length, yet morepreferably at least about 60 nucleotides in length, yet more preferablyat least about 70 nucleotides in length, yet more preferably at leastabout 80 nucleotides in length, yet more preferably at least about 90nucleotides in length, yet more preferably at least about 100nucleotides in length, yet more preferably at least about 110nucleotides in length, yet more preferably at least about 120nucleotides in length, yet more preferably at least about 130nucleotides in length, yet more preferably at least about 140nucleotides in length, yet more preferably at least about 150nucleotides in length, yet more preferably at least about 160nucleotides in length, yet more preferably at least about 170nucleotides in length, yet more preferably at least about 180nucleotides in length, yet more preferably at least about 190nucleotides in length, yet more preferably at least about 200nucleotides in length, yet more preferably at least about 250nucleotides in length, yet more preferably at least about 300nucleotides in length, yet more preferably at least about 350nucleotides in length, yet more preferably at least about 400nucleotides in length, yet more preferably at least about 450nucleotides in length, yet more preferably at least about 500nucleotides in length, yet more preferably at least about 600nucleotides in length, yet more preferably at least about 700nucleotides in length, yet more preferably at least about 800nucleotides in length, yet more preferably at least about 900nucleotides in length and yet more preferably at least about 1000nucleotides in length, wherein in this context the term “about” meansthe referenced nucleotide sequence length plus or minus 10% of thatreferenced length. It is noted that novel fragments of a PROpolypeptide-encoding nucleotide sequence may be determined in a routinemanner by aligning the PRO polypeptide-encoding nucleotide sequence withother known nucleotide sequences using any of a number of well knownsequence alignment programs and determining which PROpolypeptide-encoding nucleotide sequence fragment(s) are novel. All ofsuch PRO polypeptide-encoding nucleotide sequences are contemplatedherein. Also contemplated are the PRO polypeptide fragments encoded bythese nucleotide molecule fragments, preferably those PRO polypeptidefragments that comprise a binding site for an anti-PRO antibody.

In another embodiment, the invention provides isolated PRO polypeptideencoded by any of the isolated nucleic acid sequences hereinaboveidentified.

In a certain aspect, the invention concerns an isolated PRO polypeptide,comprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to an aminoacid sequence encoded by any of the human protein cDNAs deposited withthe ATCC as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence scoring at least about 80% positives,preferably at least about 81% positives, more preferably at least about82% positives, yet more preferably at least about 83% positives, yetmore preferably at least about 84% positives, yet more preferably atleast about 85% positives, yet more preferably at least about 86%positives, yet more preferably at least about 87% positives, yet morepreferably at least about 88% positives, yet more preferably at leastabout 89% positives, yet more preferably at least about 90% positives,yet more preferably at least about 91% positives, yet more preferably atleast about 92% positives, yet more preferably at least about 93%positives, yet more preferably at least about 94% positives, yet morepreferably at least about 95% positives, yet more preferably at leastabout 96% positives, yet more preferably at least about 97% positives,yet more preferably at least about 98% positives and yet more preferablyat least about 99% positives when compared with the amino acid sequenceof a PRO polypeptide having a full-length amino acid sequence asdisclosed herein, an amino acid sequence lacking the signal peptide asdisclosed herein or an extracellular domain of a transmembrane protein,with or without the signal peptide, as disclosed herein.

In a specific aspect, the invention provides an isolated PRO polypeptidewithout the N-terminal signal sequence and/or the initiating methionineand is encoded by a nucleotide sequence that encodes such an amino acidsequence as hereinbefore described. Processes for producing the same arealso herein described, wherein those processes comprise culturing a hostcell comprising a vector which comprises the appropriate encodingnucleic acid molecule under conditions suitable for expression of thePRO polypeptide and recovering the PRO polypeptide from the cellculture.

Another aspect the invention provides an isolated PRO polypeptide whichis either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are also hereindescribed, wherein those processes comprise culturing a host cellcomprising a vector which comprises the appropriate encoding nucleicacid molecule under conditions suitable for expression of the PROpolypeptide and recovering the PRO polypeptide from the cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PRO antibodyor a small molecule.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists to a PRO polypeptide which comprise contactingthe PRO polypeptide with a candidate molecule and monitoring abiological activity mediated by said PRO polypeptide. Preferably, thePRO polypeptide is a native PRO polypeptide.

In a still further embodiment, the invention concerns a composition ofmatter comprising a PRO polypeptide, or an agonist or antagonist of aPRO polypeptide as herein described, or an anti-PRO antibody, incombination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

Another embodiment of the present invention is directed to the use of aPRO polypeptide, or an agonist or antagonist thereof as hereinbeforedescribed, or an anti-PRO antibody, for the preparation of a medicamentuseful in the treatment of a condition which is responsive to the PROpolypeptide, an agonist or antagonist thereof or an anti-PRO antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequencePRO211 cDNA, wherein SEQ ID NO:1 is a clone designated herein as“DNA32292-1131”.

FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from thecoding sequence of SEQ ID NO:1 shown in FIG. 1.

FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequencePRO217 cDNA, wherein SEQ ID NO:3 is a clone designated herein as“DNA33094-1131”.

FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from thecoding sequence of SEQ ID NO:3 shown in FIG. 3.

FIG. 5 shows a nucleotide sequence (SEQ ID NO:11) of a native sequencePRO230 cDNA, wherein SEQ ID NO:11 is a clone designated herein as“DNA33223-1136”.

FIG. 6 shows the amino acid sequence (SEQ ID NO:12) derived from thecoding sequence of SEQ ID NO:11 shown in FIG. 5.

FIG. 7 shows a nucleotide sequence designated herein as DNA20088 (SEQ IDNO:13).

FIG. 8 shows a nucleotide sequence (SEQ ID NO:17) of a native sequencePRO232 cDNA, wherein SEQ ID NO:17 is a clone designated herein as“DNA34435-1140”.

FIG. 9 shows the amino acid sequence (SEQ ID NO:18) derived from thecoding sequence of SEQ ID NO:17 shown in FIG. 8.

FIG. 10 shows a nucleotide sequence (SEQ ID NO:22) of a native sequencePRO187 cDNA, wherein SEQ ID NO:22 is a clone designated herein as“DNA27864-1155”.

FIG. 11 shows the amino acid sequence (SEQ ID NO:23) derived from thecoding sequence of SEQ ID NO:22 shown in FIG. 10.

FIG. 12 shows a nucleotide sequence (SEQ ID NO:27) of a native sequencePRO265 cDNA, wherein SEQ ID NO:27 is a clone designated herein as“DNA36350-1158”.

FIG. 13 shows the amino acid sequence (SEQ ID NO:28) derived from thecoding sequence of SEQ ID NO:27 shown in FIG. 12.

FIG. 14 shows a nucleotide sequence (SEQ ID NO:33) of a native sequencePRO219 cDNA, wherein SEQ ID NO:33 is a clone designated herein as“DNA32290-1164”.

FIG. 15 shows the amino acid sequence (SEQ ID NO:34) derived from thecoding sequence of SEQ ID NO:33 shown in FIG. 14.

FIG. 16 shows a nucleotide sequence (SEQ ID NO:38) of a native sequencePRO246 cDNA, wherein SEQ ID NO:38 is a clone designated herein as“DNA35639-1172”.

FIG. 17 shows the amino acid sequence (SEQ ID NO:39) derived from thecoding sequence of SEQ ID NO:38 shown in FIG. 16.

FIG. 18 shows a nucleotide sequence (SEQ ID NO:48) of a native sequencePRO228 cDNA, wherein SEQ ID NO:48 is a clone designated herein as“DNA33092-1202”.

FIG. 19 shows the amino acid sequence (SEQ ID NO:49) derived from thecoding sequence of SEQ ID NO:48 shown in FIG. 18.

FIG. 20 shows a nucleotide sequence designated herein as DNA21951 (SEQID NO:50).

FIG. 21 shows a nucleotide sequence (SEQ ID NO:58) of a native sequencePRO533 cDNA, wherein SEQ ID NO:58 is a clone designated herein as“DNA49435-1219”.

FIG. 22 shows the amino acid sequence (SEQ ID NO:59) derived from thecoding sequence of SEQ ID NO:58 shown in FIG. 21.

FIG. 23 shows a nucleotide sequence (SEQ ID NO:63) of a native sequencePRO245 cDNA, wherein SEQ ID NO:63 is a clone designated herein as“DNA35638-1141”.

FIG. 24 shows the amino acid sequence (SEQ ID NO:64) derived from thecoding sequence of SEQ ID NO:63 shown in FIG. 23.

FIG. 25 shows a nucleotide sequence (SEQ ID NO:68) of a native sequencePRO220 cDNA, wherein SEQ ID NO:68 is a clone designated herein as“DNA32298-1132”.

FIG. 26 shows the amino acid sequence (SEQ ID NO:69) derived from thecoding sequence of SEQ ID NO:68 shown in FIG. 25.

FIG. 27 shows a nucleotide sequence (SEQ ID NO:70) of a native sequencePRO221 cDNA, wherein SEQ ID NO:70 is a clone designated herein as“DNA33089-1132”.

FIG. 28 shows the amino acid sequence (SEQ ID NO:71) derived from thecoding sequence of SEQ ID NO:70 shown in FIG. 27.

FIG. 29 shows a nucleotide sequence (SEQ ID NO:72) of a native sequencePRO227 cDNA, wherein SEQ ID NO:72 is a clone designated herein as“DNA33786-1132”.

FIG. 30 shows the amino acid sequence (SEQ ID NO:73) derived from thecoding sequence of SEQ ID NO:72 shown in FIG. 29.

FIG. 31 shows a nucleotide sequence (SEQ ID NO:83) of a native sequencePRO258 cDNA, wherein SEQ ID NO:83 is a clone designated herein as“DNA35918-1174”.

FIG. 32 shows the amino acid sequence (SEQ ID NO:84) derived from thecoding sequence of SEQ ID NO:83 shown in FIG. 31.

FIG. 33 shows a nucleotide sequence (SEQ ID NO:90) of a native sequencePRO266 cDNA, wherein SEQ ID NO:90 is a clone designated herein as“DNA37150-1178”.

FIG. 34 shows the amino acid sequence (SEQ ID NO:91) derived from thecoding sequence of SEQ ID NO:90 shown in FIG. 33.

FIG. 35 shows a nucleotide sequence (SEQ ID NO:95) of a native sequencePRO269 cDNA, wherein SEQ ID NO:95 is a clone designated herein as“DNA38260-1180”.

FIG. 36 shows the amino acid sequence (SEQ ID NO:96) derived from thecoding sequence of SEQ ID NO:95 shown in FIG. 35.

FIG. 37 shows a nucleotide sequence (SEQ ID NO:103) of a native sequencePRO287 cDNA, wherein SEQ ID NO:103 is a clone designated herein as“DNA39969-1185”.

FIG. 38 shows the amino acid sequence (SEQ ID NO:104) derived from thecoding sequence of SEQ 25 ID NO:103 shown in FIG. 37.

FIG. 39 shows a nucleotide sequence (SEQ ID NO:108) of a native sequencePRO214 cDNA, wherein SEQ ID NO:108 is a clone designated herein as“DNA32286-1191”.

FIG. 40 shows the amino acid sequence (SEQ ID NO:109) derived from thecoding sequence of SEQ ID NO:108 shown in FIG. 39.

FIG. 41 shows a nucleotide sequence (SEQ ID NO:113) of a native sequencePRO317 cDNA, wherein SEQ ID NO:113 is a clone designated herein as“DNA33461-1199”.

FIG. 42 shows the amino acid sequence (SEQ ID NO:114) derived from thecoding sequence of SEQ ID NO:113 shown in FIG. 41.

FIG. 43 shows a nucleotide sequence (SEQ ID NO:118) of a native sequencePRO301 cDNA, wherein SEQ ID NO:118 is a clone designated herein as“DNA40628-1216”.

FIG. 44 shows the amino acid sequence (SEQ ID NO:119) derived from thecoding sequence of SEQ ID NO:118 shown in FIG. 43.

FIG. 45 shows a nucleotide sequence (SEQ ID NO:126) of a native sequencePRO224 cDNA, wherein SEQ ID NO:126 is a clone designated herein as“DNA33221-1133”.

FIG. 46 shows the amino acid sequence (SEQ ID NO:127) derived from thecoding sequence of SEQ ID NO:126 shown in FIG. 45.

FIG. 47 shows a nucleotide sequence (SEQ ID NO:131) of a native sequencePRO222 cDNA, wherein SEQ ID NO:131 is a clone designated herein as“DNA33107-1135”.

FIG. 48 shows the amino acid sequence (SEQ ID NO:132) derived from thecoding sequence of SEQ ID NO:131 shown in FIG. 47.

FIG. 49 shows a nucleotide sequence (SEQ ID NO:136) of a native sequencePRO234 cDNA, wherein SEQ ID NO:136 is a clone designated herein as“DNA35557-1137”.

FIG. 50 shows the amino acid sequence (SEQ ID NO:137) derived from thecoding sequence of SEQ ID NO:136 shown in FIG. 49.

FIG. 51 shows a nucleotide sequence (SEQ ID NO:141) of a native sequencePRO231 cDNA, wherein SEQ ID NO:141 is a clone designated herein as“DNA34434-1139”.

FIG. 52 shows the amino acid sequence (SEQ ID NO:142) derived from thecoding sequence of SEQ ID NO:141 shown in FIG. 51.

FIG. 53 shows a nucleotide sequence (SEQ ID NO:147) of a native sequencePRO229 cDNA, wherein SEQ ID NO:147 is a clone designated herein as“DNA33100-1159”.

FIG. 54 shows the amino acid sequence (SEQ ID NO:148) derived from thecoding sequence of SEQ ID NO:147 shown in FIG. 53.

FIG. 55 shows a nucleotide sequence (SEQ ID NO:152) of a native sequencePRO238 cDNA, wherein SEQ ID NO:152 is a clone designated herein as“DNA35600-1162”.

FIG. 56 shows the amino acid sequence (SEQ ID NO:153) derived from thecoding sequence of SEQ ID NO:152 shown in FIG. 55.

FIG. 57 shows a nucleotide sequence (SEQ ID NO:158) of a native sequencePRO233 cDNA, wherein SEQ ID NO:158 is a clone designated herein as“DNA34436-1238”.

FIG. 58 shows the amino acid sequence (SEQ ID NO:159) derived from thecoding sequence of SEQ ID NO:158 shown in FIG. 57.

FIG. 59 shows a nucleotide sequence (SEQ ID NO:163) of a native sequencePRO223 cDNA, wherein SEQ ID NO:163 is a clone designated herein as“DNA33206-1165”.

FIG. 60 shows the amino acid sequence (SEQ ID NO:164) derived from thecoding sequence of SEQ ID NO:163 shown in FIG. 59.

FIG. 61 shows a nucleotide sequence (SEQ ID NO:169) of a native sequencePRO235 cDNA, wherein SEQ ID NO:169 is a clone designated herein as“DNA35558-1167”.

FIG. 62 shows the amino acid sequence (SEQ ID NO:170) derived from thecoding sequence of SEQ ID NO:169 shown in FIG. 61.

FIG. 63 shows a nucleotide sequence (SEQ ID NO:174) of a native sequencePRO236 cDNA, wherein SEQ ID NO:174 is a clone designated herein as“DNA35599-1168”.

FIG. 64 shows the amino acid sequence (SEQ ID NO:175) derived from thecoding sequence of SEQ ID NO:174 shown in FIG. 63.

FIG. 65 shows a nucleotide sequence (SEQ ID NO:176) of a native sequencePRO262 cDNA, wherein SEQ ID NO:176 is a clone designated herein as“DNA36992-1168”.

FIG. 66 shows the amino acid sequence (SEQ ID NO:177) derived from thecoding sequence of SEQ ID NO:176 shown in FIG. 65.

FIG. 67 shows a nucleotide sequence (SEQ ID NO:184) of a native sequencePRO239 cDNA, wherein SEQ ID NO:184 is a clone designated herein as“DNA34407-1169”.

FIG. 68 shows the amino acid sequence (SEQ ID NO:185) derived from thecoding sequence of SEQ ID NO:184 shown in FIG. 67.

FIG. 69 shows a nucleotide sequence (SEQ ID NO:189) of a native sequencePRO257 cDNA, wherein SEQ ID NO:189 is a clone designated herein as“DNA35841-1173”.

FIG. 70 shows the amino acid sequence (SEQ ID NO:190) derived from thecoding sequence of SEQ ID NO:189 shown in FIG. 69.

FIG. 71 shows a nucleotide sequence (SEQ ID NO:194) of a native sequencePRO260 cDNA, wherein SEQ ID NO:194 is a clone designated herein as“DNA33470-1175”.

FIG. 72 shows the amino acid sequence (SEQ ID NO:195) derived from thecoding sequence of SEQ ID NO:194 shown in FIG. 71.

FIG. 73 shows a nucleotide sequence (SEQ ID NO:200) of a native sequencePRO263 cDNA, wherein SEQ ID NO:200 is a clone designated herein as“DNA34431-1177”.

FIG. 74 shows the amino acid sequence (SEQ ID NO:201) derived from thecoding sequence of SEQ ID NO:200 shown in FIG. 73.

FIG. 75 shows a nucleotide sequence (SEQ ID NO:206) of a native sequencePRO270 cDNA, wherein SEQ ID NO:206 is a clone designated herein as“DNA39510-1181”.

FIG. 76 shows the amino acid sequence (SEQ ID NO:207) derived from thecoding sequence of SEQ ID NO:206 shown in FIG. 75.

FIG. 77 shows a nucleotide sequence (SEQ ID NO:212) of a native sequencePRO271 cDNA, wherein SEQ ID NO:212 is a clone designated herein as“DNA39423-1182”.

FIG. 78 shows the amino acid sequence (SEQ ID NO:213) derived from thecoding sequence of SEQ ID NO:212 shown in FIG. 77.

FIG. 79 shows a nucleotide sequence (SEQ ID NO:220) of a native sequencePRO272 cDNA, wherein SEQ ID NO:220 is a clone designated herein as“DNA40620-1183”.

FIG. 80 shows the amino acid sequence (SEQ ID NO:221) derived from thecoding sequence of SEQ ID NO:220 shown in FIG. 79.

FIG. 81 shows a nucleotide sequence (SEQ ID NO:226) of a native sequencePRO294 cDNA, wherein SEQ ID NO:226 is a clone designated herein as“DNA40604-1187”.

FIG. 82 shows the amino acid sequence (SEQ ID NO:227) derived from thecoding sequence of SEQ ID NO:226 shown in FIG. 81.

FIG. 83 shows a nucleotide sequence (SEQ ID NO:235) of a native sequencePRO295 cDNA, wherein SEQ ID NO:235 is a clone designated herein as“DNA38268-1188”.

FIG. 84 shows the amino acid sequence (SEQ ID NO:236) derived from thecoding sequence of SEQ ID NO:235 shown in FIG. 83.

FIG. 85 shows a nucleotide sequence (SEQ ID NO:244) of a native sequencePRO293 cDNA, wherein SEQ ID NO:244 is a clone designated herein as“DNA37151-1193”.

FIG. 86 shows the amino acid sequence (SEQ ID NO:245) derived from thecoding sequence of SEQ ID NO:244 shown in FIG. 85.

FIG. 87 shows a nucleotide sequence (SEQ ID NO:249) of a native sequencePRO247 cDNA, wherein SEQ ID NO:249 is a clone designated herein as“DNA35673-1201”.

FIG. 88 shows the amino acid sequence (SEQ ID NO:250) derived from thecoding sequence of SEQ ID NO:249 shown in FIG. 87.

FIG. 89 shows a nucleotide sequence (SEQ ID NO:254) of a native sequencePRO302 cDNA, wherein SEQ ID NO:254 is a clone designated herein as“DNA40370-1217”.

FIG. 90 shows the amino acid sequence (SEQ ID NO:255) derived from thecoding sequence of SEQ ID NO:254 shown in FIG. 89.

FIG. 91 shows a nucleotide sequence (SEQ ID NO:256) of a native sequencePRO303 cDNA, wherein SEQ ID NO:256 is a clone designated herein as“DNA42551-1217”.

FIG. 92 shows the amino acid sequence (SEQ ID NO:257) derived from thecoding sequence of SEQ ID NO:256 shown in FIG. 91.

FIG. 93 shows a nucleotide sequence (SEQ ID NO:258) of a native sequencePRO304 cDNA, wherein SEQ ID NO:258 is a clone designated herein as“DNA39520-1217”.

FIG. 94 shows the amino acid sequence (SEQ ID NO:259) derived from thecoding sequence of SEQ ID NO:258 shown in FIG. 93.

FIG. 95 shows a nucleotide sequence (SEQ ID NO:260) of a native sequencePRO307 cDNA, wherein SEQ ID NO:260 is a clone designated herein as“DNA41225-1217”.

FIG. 96 shows the amino acid sequence (SEQ ID NO:261) derived from thecoding sequence of SEQ ID NO:260 shown in FIG. 95.

FIG. 97 shows a nucleotide sequence (SEQ ID NO:262) of a native sequencePRO343 cDNA, wherein SEQ ID NO:262 is a clone designated herein as“DNA43318-1217”.

FIG. 98 shows the amino acid sequence (SEQ ID NO:263) derived from thecoding sequence of SEQ ID NO:262 shown in FIG. 97.

FIG. 99 shows a nucleotide sequence (SEQ ID NO:284) of a native sequencePRO328 cDNA, wherein SEQ ID NO:284 is a clone designated herein as“DNA40587-1231”.

FIG. 100 shows the amino acid sequence (SEQ ID NO:285) derived from thecoding sequence of SEQ ID NO:284 shown in FIG. 99.

FIG. 101 shows a nucleotide sequence (SEQ ID NO:289) of a nativesequence PRO335 cDNA, wherein SEQ ID NO:289 is a clone designated hereinas “DNA41388-1234”.

FIG. 102 shows the amino acid sequence (SEQ ID NO:290) derived from thecoding sequence of SEQ ID NO:289 shown in FIG. 101.

FIG. 103 shows a nucleotide sequence (SEQ ID NO:291) of a nativesequence PRO331 cDNA, wherein SEQ ID NO:291 is a clone designated hereinas “DNA40981-1234”.

FIG. 104 shows the amino acid sequence (SEQ ID NO:292) derived from thecoding sequence of SEQ ID NO:291 shown in FIG. 103.

FIG. 105 shows a nucleotide sequence (SEQ ID NO:293) of a nativesequence PRO326 cDNA, wherein SEQ ID NO:293 is a clone designated hereinas “DNA37140-1234”.

FIG. 106 shows the amino acid sequence (SEQ ID NO:294) derived from thecoding sequence of SEQ ID NO:293 shown in FIG. 105.

FIG. 107 shows a nucleotide sequence (SEQ ID NO:309) of a nativesequence PRO332 cDNA, wherein SEQ ID NO:309 is a clone designated hereinas “DNA40982-1235”.

FIG. 108 shows the amino acid sequence (SEQ ID NO:310) derived from thecoding sequence of SEQ ID NO:309 shown in FIG. 107.

FIG. 109 shows a nucleotide sequence (SEQ ID NO:314) of a nativesequence PRO334 cDNA, wherein SEQ ID NO:314 is a clone designated hereinas “DNA41379-1236”.

FIG. 110 shows the amino acid sequence (SEQ ID NO:315) derived from thecoding sequence of SEQ ID NO:314 shown in FIG. 109.

FIG. 111 shows a nucleotide sequence (SEQ ID NO:319) of a nativesequence PRO346 cDNA, wherein SEQ ID NO:319 is a clone designated hereinas “DNA44167-1243”.

FIG. 112 shows the amino acid sequence (SEQ ID NO:320) derived from thecoding sequence of SEQ ID NO:319 shown in FIG. 111.

FIG. 113 shows a nucleotide sequence (SEQ ID NO:324) of a nativesequence PRO268 cDNA, wherein SEQ ID NO:324 is a clone designated hereinas “cDNA39427-1179”.

FIG. 114 shows the amino acid sequence (SEQ ID NO:325) derived from thecoding sequence of SEQ ID NO:324 shown in FIG. 113.

FIG. 115 shows a nucleotide sequence (SEQ ID NO:331) of a nativesequence PRO330 cDNA, wherein SEQ ID NO:331 is a clone designated hereinas “DNA40603-1232”.

FIG. 116 shows the amino acid sequence (SEQ ID NO:332) derived from thecoding sequence of SEQ ID NO:331 shown in FIG. 115.

FIG. 117 shows a nucleotide sequence (SEQ ID NO:338) of a nativesequence PRO339 cDNA, wherein SEQ ID NO:338 is a clone designated hereinas “DNA43466-1225”.

FIG. 118 shows the amino acid sequence (SEQ ID NO:339) derived from thecoding sequence of SEQ ID NO:338 shown in FIG. 117.

FIG. 119 shows a nucleotide sequence (SEQ ID NO:340) of a nativesequence PRO310 cDNA, wherein SEQ ID NO:340 is a clone designated hereinas “DNA43046-1225”.

FIG. 120 shows the amino acid sequence (SEQ ID NO:341) derived from thecoding sequence of SEQ ID NO:340 shown in FIG. 119.

FIG. 121 shows a nucleotide sequence (SEQ ID NO:376) of a nativesequence PRO244 cDNA, wherein SEQ ID NO:376 is a clone designated hereinas “DNA35668-1171”.

FIG. 122 shows the amino acid sequence (SEQ ID NO:377) derived from thecoding sequence of SEQ ID NO:376 shown in FIG. 121.

FIG. 123 shows a nucleotide sequence (SEQ ID NO:422) of a nativesequence PRO1868 cDNA, wherein SEQ ID NO:422 is a clone designatedherein as “DNA77624-2515”.

FIG. 124 shows the amino acid sequence (SEQ ID NO:423) derived from thecoding sequence of SEQ ID NO:422 shown in FIG. 123.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

The terms “PRO polypeptide” and “PRO” as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number) refersto specific polypeptide sequences as described herein. The terms“PRO/number polypeptide” and “PRO/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The PRO polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods.

A “native sequence PRO polypeptide” comprises a polypeptide having thesame amino acid sequence as the corresponding PRO polypeptide derivedfrom nature. Such native sequence PRO polypeptides can be isolated fromnature or can be produced by recombinant or synthetic means. The term“native sequence PRO polypeptide” specifically encompassesnaturally-occurring truncated or secreted forms of the specific PROpolypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In variousembodiments of the invention, the native sequence PRO polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons are shown in bold font andunderlined in the figures. However, while the PRO polypeptide disclosedin the accompanying figures are shown to begin with methionine residuesdesignated herein as amino acid position 1 in the figures, it isconceivable and possible that other methionine residues located eitherupstream or downstream from the amino acid position 1 in the figures maybe employed as the starting amino acid residue for the PRO polypeptides.

The PRO polypeptide “extracellular domain” or “ECD” refers to a form ofthe PRO polypeptide which is essentially free of the transmembrane andcytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have lessthan 1% of such transmembrane and/or cytoplasmic domains and preferably,will have less than 0.5% of such domains. It will be understood that anytransmembrane domains identified for the PRO polypeptides of the presentinvention are identified pursuant to criteria routinely employed in theart for identifying that type of hydrophobic domain. The exactboundaries of a transmembrane domain may vary but most likely by no morethan about 5 amino acids at either end of the domain as initiallyidentified herein. Optionally, therefore, an extracellular domain of aPRO polypeptide may contain from about 5 or fewer amino acids on eitherside of the transmembrane domain/extracellular domain boundary asidentified in the Examples or specification and such polypeptides, withor without the associated signal peptide, and nucleic acid encodingthem, are contemplated by the present invention.

The approximate location of the “signal peptides” of the various PROpolypeptides disclosed herein are shown in the present specificationand/or the accompanying figures. It is noted, however, that theC-terminal boundary of a signal peptide may vary, but most likely by nomore than about 5 amino acids on either side of the signal peptideC-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)).Moreover, it is also recognized that, in some cases, cleavage of asignal sequence from a secreted polypeptide is not entirely uniform,resulting in more than one secreted species. These mature polypeptides,where the signal peptide is cleaved within no more than about 5 aminoacids on either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

“PRO polypeptide variant” means an active PRO polypeptide as definedabove or below having at least about 80% amino acid sequence identitywith a full-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptides wherein oneor more amino acid residues are added, or deleted, at the N- orC-terminus of the full-length native amino acid sequence. Ordinarily, aPRO polypeptide variant will have at least about 80% amino acid sequenceidentity, preferably at least about 81% amino acid sequence identity,more preferably at least about 82% amino acid sequence identity, morepreferably at least about 83% amino acid sequence identity, morepreferably at least about 84% amino acid sequence identity, morepreferably at least about 85% amino acid sequence identity, morepreferably at least about 86% amino acid sequence identity, morepreferably at least about 87% amino acid sequence identity, morepreferably at least about 88% amino acid sequence identity, morepreferably at least about 89% amino acid sequence identity, morepreferably at least about 90% amino acid sequence identity, morepreferably at least about 91% amino acid sequence identity, morepreferably at least about 92% amino acid sequence identity, morepreferably at least about 93% amino acid sequence identity, morepreferably at least about 94% amino acid sequence identity, morepreferably at least about 95% amino acid sequence identity, morepreferably at least about 96% amino acid sequence identity, morepreferably at least about 97% amino acid sequence identity, morepreferably at least about 98% amino acid sequence identity and mostpreferably at least about 99% amino acid sequence identity with afull-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length PRO polypeptide sequenceas disclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, often at least about 20 amino acids inlength, more often at least about 30 amino acids in length, more oftenat least about 40 amino acids in length, more often at least about 50amino acids in length, more often at least about 60 amino acids inlength, more often at least about 70 amino acids in length, more oftenat least about 80 amino acids in length, more often at least about 90amino acids in length, more often at least about 100 amino acids inlength, more often at least about 150 amino acids in length, more oftenat least about 200 amino acids in length, more often at least about 300amino acids in length, or more.

“Percent (%) amino acid sequence identity” with respect to the PROpolypeptide sequences identified herein is defined as the percentage ofamino acid residues in a candidate sequence that are identical with theamino acid residues in the specific PRO polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. As examples of % amino acid sequence identitycalculations using this method, Tables 2 and 3 demonstrate how tocalculate the % amino acid sequence identity of the amino acid sequencedesignated “Comparison Protein” to the amino acid sequence designated“PRO”, wherein “PRO” represents the amino acid sequence of ahypothetical PRO polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“PRO” polypeptide of interest is being compared, and “X, “Y” and “Z”each represent different hypothetical amino acid residues.

Unless specifically stated otherwise, all % amino acid sequence identityvalues used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, % aminoacid sequence identity values may also be obtained as described below byusing the WU-BLAST-2 computer program (Altschul et al., Methods inEnzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parametersare set to the default values. Those not set to default values, i.e.,the adjustable parameters, are set with the following values: overlapspan=1, overlap fraction=0.125, word threshold (T)=11, and scoringmatrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequenceidentity value is determined by dividing (a) the number of matchingidentical amino acid residues between the amino acid sequence of the PROpolypeptide of interest having a sequence derived from the native PROpolypeptide and the comparison amino acid sequence of interest (i.e.,the sequence against which the PRO polypeptide of interest is beingcompared which may be a PRO variant polypeptide) as determined byWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest. For example, in the statement “a polypeptidecomprising an the amino acid sequence A which has or having at least 80%amino acid sequence identity to the amino acid sequence B”, the aminoacid sequence A is the comparison amino acid sequence of interest andthe amino acid sequence B is the amino acid sequence of the PROpolypeptide of interest.

Percent amino acid sequence identity may also be determined using thesequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters,wherein all of those search parameters are set to default valuesincluding, for example, unmask=yes, strand=all, expected occurrences=10,minimum low complexity length=15/5, multi-pass e-value =0.01, constantfor multi-pass=25, dropoff for final gapped alignment =25 and scoringmatrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times. the fraction X/Y

where X is the number of amino acid residues scored as identical matchesby the sequence alignment program NCBI-BLAST2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

“PRO variant polynucleotide” or “PRO variant nucleic acid sequence”means a nucleic acid molecule which encodes an active PRO polypeptide asdefined below and which has at least about 80% nucleic acid sequenceidentity with a nucleotide acid sequence encoding a full-length nativesequence PRO polypeptide sequence as disclosed herein, a full-lengthnative sequence PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Ordinarily,a PRO variant polynucleotide will have at least about 80% nucleic acidsequence identity, more preferably at least about 81% nucleic acidsequence identity, more preferably at least about 82% nucleic acidsequence identity, more preferably at least about 83% nucleic acidsequence identity, more preferably at least about 84% nucleic acidsequence identity, more preferably at least about 85% nucleic acidsequence identity, more preferably at least about 86% nucleic acidsequence identity, more preferably at least about 87% nucleic acidsequence identity, more preferably at least about 88% nucleic acidsequence identity, more preferably at least about 89% nucleic acidsequence identity, more preferably at least about 90% nucleic acidsequence identity, more preferably at least about 91% nucleic acidsequence identity, more preferably at least about 92% nucleic acidsequence identity, more preferably at least about 93% nucleic acidsequence identity, more preferably at least about 94% nucleic acidsequence identity, more preferably at least about 95% nucleic acidsequence identity, more preferably at least about 96% nucleic acidsequence identity, more preferably at least about 97% nucleic acidsequence identity, more preferably at least about 98% nucleic acidsequence identity and yet more preferably at least about 99% nucleicacid sequence identity with a nucleic acid sequence encoding afull-length native sequence PRO polypeptide sequence as disclosedherein, a full-length native sequence PRO polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, often at least about 60 nucleotides in length,more often at least about 90 nucleotides in length, more often at leastabout 120 nucleotides in length, more often at least about 150nucleotides in length, more often at least about 180 nucleotides inlength, more often at least about 210 nucleotides in length, more oftenat least about 240 nucleotides in length, more often at least about 270nucleotides in length, more often at least about 300 nucleotides inlength, more often at least about 450 nucleotides in length, more oftenat least about 600 nucleotides in length, more often at least about 900nucleotides in length, or more.

“Percent (%) nucleic acid sequence identity” with respect toPRO-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the PRO nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by thesequence alignment program ALIGN-2 in that program's alignment of C andD, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations, Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”,wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “PRO-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides.

Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, %nucleic acid sequence identity values may also be obtained as describedbelow by using the WU-BLAST-2 computer program (Altschul et al., Methodsin Enzymology 266:460480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleicacid sequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence of thePRO polypeptide-encoding nucleic acid molecule of interest having asequence derived from the native sequence PRO polypeptide-encodingnucleic acid and the comparison nucleic acid molecule of interest (i.e.,the sequence against which the PRO polypeptide-encoding nucleic acidmolecule of interest is being compared which may be a variant PROpolynucleotide) as determined by WU-BLAST-2 by (b) the total number ofnucleotides of the PRO polypeptide-encoding nucleic acid molecule ofinterest. For example, in the statement “an isolated nucleic acidmolecule comprising a nucleic acid sequence A which has or having atleast 80% nucleic acid sequence identity to the nucleic acid sequenceB”, the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acid sequenceof the PRO polypeptide-encoding nucleic acid molecule of interest.

Percent nucleic acid sequence identity may also be determined using thesequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters,wherein all of those search parameters are set to default valuesincluding, for example, unmask=yes, strand=all, expected occurrences=10,minimum low complexity length=15/5, multi-pass e-value=0.01, constantfor multi-pass=25, dropoff for final gapped alignment=25 and scoringmatrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for sequence comparisons,the % nucleic acid sequence identity of a given nucleic acid sequence Cto, with, or against a given nucleic acid sequence D (which canalternatively be phrased as a given nucleic acid sequence C that has orcomprises a certain % nucleic acid sequence identity to, with, oragainst a given nucleic acid sequence D) is calculated as follows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by thesequence alignment program NCBI-BLAST2 in that program's alignment of Cand D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C.

In other embodiments, PRO variant polynucleotides are nucleic acidmolecules that encode an active PRO polypeptide and which are capable ofhybridizing, preferably under stringent hybridization and washconditions, to nucleotide sequences encoding a full-length PROpolypeptide as disclosed herein. PRO variant polypeptides may be thosethat are encoded by a PRO variant polynucleotide.

The term “positives”, in the context of sequence comparison performed asdescribed above, includes residues in the sequences compared that arenot identical but have similar properties (e.g. as a result ofconservative substitutions, see Table 6 below). For purposes herein, the% value of positives is determined by dividing (a) the number of aminoacid residues scoring a positive value between the PRO polypeptide aminoacid sequence of interest having a sequence derived from the native PROpolypeptide sequence and the comparison amino acid sequence of interest(i.e., the amino acid sequence against which the PRO polypeptidesequence is being compared) as determined in the BLOSUM62 matrix ofWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest.

Unless specifically stated otherwise, the % value of positives iscalculated as described in the immediately preceding paragraph. However,in the context of the amino acid sequence identity comparisons performedas described for ALIGN-2 and NCBI-BLAST-2 above, includes amino acidresidues in the sequences compared that are not only identical, but alsothose that have similar properties. Amino acid residues that score apositive value to an amino acid residue of interest are those that areeither identical to the amino acid residue of interest or are apreferred substitution (as defined in Table 6 below) of the amino acidresidue of interest.

For amino acid sequence comparisons using ALIGN-2 or NCBI-BLAST2, the %value of positives of a given amino acid sequence A to, with, or againsta given amino acid sequence B (which can alternatively be phrased as agiven amino acid sequence A that has or comprises a certain % positivesto, with, or against a given amino acid sequence B) is calculated asfollows:

100 times the fraction X/Y

where X is the number of amino acid residues scoring a positive value asdefined above by the sequence alignment program ALIGN-2 or NCBI-BLAST2in that program's alignment of A and B, and where Y is the total numberof amino acid residues in B. It will be appreciated that where thelength of amino acid sequence A is not equal to the length of amino acidsequence B, the % positives of A to B will not equal the % positives ofB to A.

“Isolated, ” when used to describe the various polypeptides disclosedherein, means polypeptide that has been identified and separated and/orrecovered from a component of its natural environment. Contaminantcomponents of its natural environment are materials that would typicallyinterfere with diagnostic or therapeutic uses for the polypeptide, andmay include enzymes, hormones, and other proteinaceous ornon-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PRO polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

An “isolated” PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

The term “control sequences” refers to DNA sequences necessary for theexpression of an operably linked coding sequence in a particular hostorganism. The control sequences that are suitable for prokaryotes, forexample, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are contiguous, and, in thecase of a secretory leader, contiguous and in reading phase. However,enhancers do not have to be contiguous. Linking is accomplished byligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

The term “antibody” is used in the broadest sense and specificallycovers, for example, single anti-PRO monoclonal antibodies (includingagonist, antagonist, and neutralizing antibodies), anti-PRO antibodycompositions with polyepitopic specificity, single chain anti-PROantibodies, and fragments of anti-PRO antibodies (see below). The term“monoclonal antibody” as used herein refers to an antibody obtained froma population of substantially homogeneous antibodies, i.e., theindividual antibodies comprising the population are identical except forpossible naturally-occurring mutations that may be present in minoramounts.

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

“Stringent conditions” or “high stringency conditions”, as definedherein, may be identified by those that: (1) employ low ionic strengthand high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt'ssolution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10%dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodiumchloride/sodium citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

“Moderately stringent conditions” may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York: ColdSpring Harbor Press, 1989, and include the use of washing solution andhybridization conditions (e.g., temperature, ionic strength and % SDS)less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.The tag polypeptide has enough residues to provide an epitope againstwhich an antibody can be made, yet is short enough such that it does notinterfere with activity of the polypeptide to which it is fused. The tagpolypeptide preferably also is fairly unique so that the antibody doesnot substantially cross-react with other epitopes. Suitable tagpolypeptides generally have at least six amino acid residues and usuallybetween about 8 and 50 amino acid residues (preferably, between about 10and 20 amino acid residues).

As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesins comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The inmmunoglobulin constant domain sequence inthe immunoadhesin may be obtained from any immunoglobulin, such asIgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2),IgE, IgD or IgM.

“Active” or “activity” for the purposes herein refers to form(s) of aPRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring PRO and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring PRO.

The term “antagonist” is used in the broadest sense, and includes anymolecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native PRO polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native PROpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native PROpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the PROpolypeptide.

“Treatment” refers to both therapeutic treatment and prophylactic orpreventative measures, wherein the object is to prevent or slow down(lessen) the targeted pathologic condition or disorder. Those in need oftreatment include those already with the disorder as well as those proneto have the disorder or those in whom the disorder is to be prevented.

“Chronic” administration refers to administration of the agent(s) in acontinuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of time.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

“Mammal” for purposes of treatment refers to any animal classified as amammal, including humans, domestic and farm animals, and zoo, sports, orpet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats,rabbits, etc. Preferably, the mammal is human.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers which are nontoxic to the cell or mammalbeing exposed thereto at the dosages and concentrations employed. Oftenthe physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

“Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng.8(10): 1057-1062 [1995]); single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

Papain digestion of antibodies produces two identical antigen-bindingfragments, called “Fab” fragments, each with a single antigen-bindingsite, and a residual “Fc” fragment, a designation reflecting the abilityto crystallize readily. Pepsin treatment yields an F(ab′)₂ fragment thathas two antigen-combining sites and is still capable of cross-linkingantigen.

“Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of a dimerof one heavy- and one light-chain variable domain in tight, non-covalentassociation. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding site on thesurface of the V_(H)-V_(L) dimer. Collectively, the six CDRs conferantigen-binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab fragmentsdiffer from Fab′ fragments by the addition of a few residues at thecarboxy terminus of the heavy chain CH1 domain including one or morecysteines from the antibody hinge region. Fab′-SH is the designationherein for Fab′ in which the cysteine residue(s) of the constant domainsbear a free thiol group. F(ab′)₂ antibody fragments originally wereproduced as pairs of Fab′ fragments which have hinge cysteines betweenthem. Other chemical couplings of antibody fragments are also known.

The “light chains” of antibodies (immunoglobulins) from any vertebratespecies can be assigned to one of two clearly distinct types, calledkappa and lambda, based on the amino acid sequences of their constantdomains.

Depending on the amino acid sequence of the constant domain of theirheavy chains, immunoglobulins can be assigned to different classes.There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, andIgM, and several of these may be further divided into subclasses(isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

“Single-chain Fv” or “sFv” antibody fragments comprise the V_(H) andV_(L) domains of antibody, wherein these domains are present in a singlepolypeptide chain. Preferably, the Fv polypeptide further comprises apolypeptide linker between the V_(H)and V_(L) domains which enables thesFv to form the desired structure for antigen binding. For a review ofsFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315(1994).

The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies are described morefully in, for example, EP 404,097; WO 93/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

An “isolated” antibody is one which has been identified and separatedand/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

The word “label” when used herein refers to a detectable compound orcomposition which is conjugated directly or indirectly to the antibodyso as to generate a “labeled” antibody. The label may be detectable byitself (e.g. radioisotope labels or fluorescent labels) or, in the caseof an enzymatic label, may catalyze chemical alteration of a substratecompound or composition which is detectable.

By “solid phase” is meant a non-aqueous matrix to which the antibody ofthe present invention can adhere. Examples of solid phases encompassedherein include those formed partially or entirely of glass (e.g.,controlled pore glass), polysaccharides (e.g., agarose),polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Incertain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as a PRO polypeptide or antibody thereto) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

A “small molecule” is defined herein to have a molecular weight belowabout 500 Daltons.

“PRO317-associated disorder” refers to a pathological condition ordisease wherein PRO317 is over- or underexpressed. Such disordersinclude diseases of the female genital tract or of the endometrium of amammal, including hyperplasia, endometritis, endometriosis, wherein thepatient is at risk for infertility due to endometrial factor,endometrioma, and endometrial cancer, especially those diseasesinvolving abnormal bleeding such as a gynecological disease. They alsoinclude diseases involving angiogenesis, wherein the angiogenesisresults in a pathological condition, such as cancer involving solidtumors (the therapy for the disorder would result in decreasedvascularization and a decline in growth and metastasis of a variety oftumors). Alternatively, the angiogenesis may be beneficial, such as forischemia, especially coronary ischemia. Hence, these disorders includethose found in patients whose hearts are functioning but who have ablocked blood supply due to atherosclerotic coronary artery disease, andthose with a functioning but underperfused heart, including patientswith coronary arterial disease who are not optimal candidates forangioplasty and coronary artery by-pass surgery. The disorders alsoinclude diseases involving the kidney or originating from the kidneytissue, such as polycystic kidney disease and chronic and acute renalfailure.

TABLE 1 /*  *  * C-C increased from 12 to 15  * Z is average of EQ  * Bis average of ND  * match with stop is _M; stop-stop = 0; J (joker)match = 0  */ #define _M −8 /* value of a match with a stop */ int_day[26][26] = { /*  A B C D E F G H I J K L M N O P Q R S T U V W X Y Z*/ /* A */ { 2, 0, −2, 0, 0, −4, 1, −1, −1, 0, −1, −2, −1, 0, _M, 1, 0,−2, 1, 1, 0, 0, −6, 0, −3, 0}, /* B */ { 0, 3, −4, 3, 2, −5, 0, 1, −2,0, 0, −3, −2, 2, _M, −1, 1, 0, 0, 0, 0, −2, −5, 0, −3, 1}, /* C */ {−2,−4, 15, −5, −5, −4, −3, −3, −2, 0, −5, −6, −5, −4, _M, −3, −5, −4, 0,−2, 0, −2, −8, 0, 0, −5}, /* D */ {0, 3, −5, 4, 3, −6, 1, 1, −2, 0, 0,−4, −3, 2, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 2}, /* E */ {0, 2, −5,3, 4, −5, 0, 1, −2, 0, 0, −3, −2, 1, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0,−4, 3}, /* F */ {−4, −5, −4, −6, −5, 9, −5, −2, 1, 0, −5, 2, 0, −4, _M,−5, −5, −4, −3, −3, 0, −1, 0, 0, 7, −5}, /* G */ { 1, 0, −3, 1, 0, −5,5, −2, −3, 0, −2, −4, −3, 0, _M, −1, −1, −3, 1, 0, 0, −1, −7, 0, −5, 0},/* H */ {−1, 1, −3, 1, 1, −2, −2, 6, −2, 0, 0, −2, −2, 2, _M, 0, 3, 2,−1, −1, 0, −2, −3, 0, 0, 2}, /* I */ {−1, −2, −2, −2, −2, 1, −3, −2, 5,0, −2, 2, 2, −2, _M, −2, −2, −2, −1, 0, 0, 4, −5, 0, −1, −2}, /* J */{0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0}, /* K */ {−1, 0, −5, 0, 0, −5, −2, 0, −2, 0, 5, −3, 0, 1, _M,−1, 1, 3, 0, 0, 0, −2, −3, 0, −4, 0}, /* L */ {−2, −3, −6, −4, −3, 2,−4, −2, 2, 0, −3, 6, 4, −3, _M, −3, −2, −3, −3 , −1, 0, 2, −2, 0, −1,−2}, /* M */ {−1, −2, −5, −3, −2, 0, −3, −2, 2, 0, 0, 4, 6, −2, _M, −2,−1, 0, −2, −1, 0, 2, −4, 0, −2, −1}, /* N */ {0, 2, −4, 2, 1, −4, 0, 2,−2, 0, 1, −3, −2, 2, _M, −1, 1, 0, 1, 0, 0, −2, −4, 0, −2, 1}, /* O */{_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,}, /* P */ {1, −1, −3, −1, −1, −5,−1, 0, −2, 0, −1, −3, −2, −1,_M, 6, 0, 0, 1, 0, 0, −1, −6, 0, −5, 0}, /*Q */ {0, 1, −5, 2, 2, −5, −1, 3, −2, 0, 1, −2, −1, 1, _M, 0, 4, 1, −1,−1, 0, −2, −5, 0, −4, 3}, /* R */ {−2, 0, −4, −1, −1, −4, −3, 2, −2, 0,3, −3, 0, 0, _M, 0, 1, 6, 0, −1, 0, −2, 2, 0, −4, 0}, /* S */ { 1, 0, 0,0, 0, −3, 1, −1, −1, 0, 0, −3, −2, 1, _M, 1, −1, 0, 2, 1, 0, −1, −2, 0,−3, 0}, /* T */ { 1, 0, −2, 0, 0, −3, 0, −1, 0, 0, 0, −1, −1, 0, _M, 0,−1, −1, 1, 3, 0, 0, −5, 0, −3, 0}, /* U */ {0, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ {0, −2, −2,−2, −2, −1, −1, −2, 4, 0, −2, 2, 2, −2,_M, −1, −2, −2, −1, 0, 0, 4, −6,0, −2, −2}, /* W */ {−6, −5, −8, −7, −7, 0, −7, −3, −5, 0, −3, −2, −4,−4,_M, −6, −5, 2, −2, −5, 0, −6, 17, 0, 0, −6}, /* X */ {0, 0, 0, 0, 0,0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* Y */{−3, −3, 0, −4, −4, 7, −5, 0, −1, 0, −4, −1, −2, −2, _M, −5, −4, −4, −3,−3, 0, −2, 0, 0, 10, −4}, /* Z */ { 0, 1, −5, 2, 3, −5, 0, 2, −2, 0, 0,−2, −1, 1,_M, 0, 3, 0, 0, 0, 0, −2, −6, 0, −4, 4} }; /*  */ #include<stdio.h> #include <ctype.h> #define MAXJMP  16 /* max jumps in a diag*/ #define MAXGAP  24 /* don't continue to penalize gaps larger thanthis */ #define JMPS 1024 /* max jmps in an path */ #define MX   4 /*save if there's at least MX − 1 bases since last jmp */ #define DMAT   3/* value of matching bases */ #define DMIS   0 /* penalty for mismatchedbases */ #define DINS0   8 /* penalty for a gap */ #define DINS1   1 /*penalty per base */ #define PINS0   8 /* penalty for a gap */ #definePINS1   4 /* penalty per residue */ struct jmp { short n[MAXJMP]; /*size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /* base no. ofjmp in seq x */ /* limits seq to 2{circumflex over ( )}16 − 1 */ };struct diag { int score; /* score at last jmp */ long offset; /* offsetof prev block */ short ijmp; /* current jmp index */ struct jmp jp; /*list of jmps */ }; struct path { int spc; /* number of leading spaces */short n[JMPS]; /* size of jmp (gap) */ int x[JMPS]; /* loc of jmp (lastelem before gap) */ }; char *ofile; /* output file name */ char*namex[2]; /* seq names: getseqs() */ char *prog; /* prog name for errmsgs */ char *seqx[2];   /* seqs: getseqs() */ int dmax; /* best diag:nw() */ int dmax0; /* final diag */ int dna; /* set if dna: main() */int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /* totalgaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy; /*total size of gaps */ int smax; /* max score: nw() */ int *xbm; /*bitmap for matching */ long offset; /* current offset in jmp file */struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds pathfor seqs */ char *calloc(), *malloc(), *index(), *strcpy(); char*getseq(), *g_calloc(); /* Needleman-Wunsch alignment program  *  *usage: progs file1 file2  * where file1 and file2 are two dna or twoprotein sequences.  * The sequences can be in upper- or lower-case anmay contain ambiguity  * Any lines beginning with ‘;’, ‘>’ or ‘<’ areignored  * Max file length is 65535 (limited by unsigned short x in thejmp struct)  * A sequence with ⅓ or more of its elements ACGTU isassumed to be DNA  * Output is in the file “align.out”  *  * The programmay create a tmp file in /tmp to hold info about traceback.  * Originalversion developed under BSD 4.3 on a vax 8650  */ #include “nw.h”#include “day.h” static _dbval[26] = {1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static_pbval[26] = { 1, 2|(1< <(‘D’-‘A’))|(1< <(‘N’-‘A’)), 4, 8, 16, 32, 64,128, 256, 0×FFFFFFF, 1< <10, 1< <11, 1< <12, 1< <13, 1< <14, 1< <15, 1<<16, 1< <17, 1< <18, 1< <19, 1< <20, 1< <21, 1< <22, 1< <23, 1< <24, 1<<25|(1< <(‘E’-‘A’))|(1< <(‘Q’-‘A’)) }; main(ac, av) main int ac; char*av[]; { prog = av[0]; if(ac != 3) { fprintf(stderr, “usage: %s file1file2\n”, prog); fprintf(stderr, “where file1 and file2 are two dna ortwo protein sequences.\n”); fprintf(stderr, “The sequences can be inupper- or lower-case\n”); fprintf(stderr, “Any lines beginning with ‘;’or ‘<’ are ignored\n”); fprintf(stderr, “Output is in the file\“align.out\”\n”); exit(1); } namex[0] = av[1]; namex[1] = av[2];seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1);xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ofile = “align.out”; /* output file */ nw(); /* fill in the matrix, getthe possible jmps */ readjmps(); /* get the actual jmps */ print(); /*print stats, alignment */ cleanup(0); /* unlink any tmp files */ } /* dothe alignment, return best score: main()  * dna: values in Fitch andSmith, PNAS, 80, 1382-1386, 1983  * pro: PAM 250 values  * When scoresare equal, we prefer mismatches to any gap, prefer  * a new gap toextending an ongoing gap, and prefer a gap in seqx  * to a gap in seq y. */ nw() nw { char *px, *py;   /* seqs and ptrs */ int *ndely, *dely; /*keep track of dely */ int ndelx, delx; /* keep track of delx */ int*tmp; /* for swapping row0, row1 */ int mis; /* score for each type */int ins0, ins1; /* insertion penalties */ register id; /* diagonal index*/ register ij; /* jmp index */ register *col0, *col1; /* score forcurr, last row */ register xx, yy; /* index into seqs */ dx = ( structdiag *)g_calloc(“to get diags”, len0 + len1 + 1, sizeof(struct diag));ndely = (int *)g_calloc(“to get ndely”, len1 + 1, sizeof(int)); dely =(int *)g_calloc(“to get dely”, len1 + 1, sizeof(int)); col0 = (int*)g_calloc(“to get col0”, len1 + 1, sizeof(int)); col1 = (int*)g_calloc(“to get col1”, len1 + 1, sizeof(int)); ins0 = (dna)? DINS0 :PINS0; ins1 = (dna)? DINS1 : PlNS1; smax = −10000; if (endgaps) { for(col0[0] = dely[0] = −ins0, yy = 1; yy <= len1; yy++) { col0[yy] =dely[yy] = col0[yy−1] − ins1; ndely[yy] = yy; } col0[0] = 0; /* WatermanBull Math Biol 84 */ } else for (yy = 1; yy <= len1; yy++) dely[yy] =−ins0; /* fill in match matrix  */ for (px = seqx[0], xx = 1; xx <=len0; px++, xx++) { /* initialize first entry in col  */ if (endgaps) {if (xx == 1) col1[0] = delx = −(ins0 + ins1); else col1[0] = delx =col0[0] − ins1; ndelx = xx; } else { col1[0] = 0; delx = −ins0; ndelx =0; } for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) { mis =col0[yy−1]; if (dna) mis + = (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT : DMIS;else mis += _day[*px−‘A’][*py−‘A’]; /* update penalty for del in x seq; * favor new del over ongong del  * ignore MAXGAP if weighting endgaps */ if (endgaps || ndely[yy] < MAXGAP) { if (col0[yy] − ins0 >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } else {dely[yy] −= ins1; ndely[yy]++; } } else { if (col0[yy] − (ins0+ins1) >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } elsendely[yy]++; } /* update penalty for del in y seq;  * favor new del overongong del  */ if (endgaps || ndelx < MAXGAP) { if(col1[yy−1] − ins0 >=delx) { delx = col1[yy−1] − (ins0+ins1); ndelx = 1; } else { delx −=ins1; ndelx++; } } else { if (col1[yy−1] − (ins0+ins1) > = delx) { delx= col1[yy−1] − (ins0+ins1); ndelx = 1; } else ndelx+ +; } /* pick themaximum score; we're favoring  * mis over any del and delx over dely  */id = xx − yy + len1 − 1; if (mis >= delx && mis >= dely[yy]) col1[yy] =mis; else if (delx > = dely[yy]) { col1[yy] = delx; ij = dx[id].ijmp; if(dx[id].jp.n[0] && (!dna || (ndelx > = MAXJMP && xx >dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp+ +; if(++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset =offset; offset += sizeof(struct jmp) + sizeof(offset); } }dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx; dx[id].score = delx; }else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if (dx[id].jp.n[0] &&(!dna || (ndely[yy] > = MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis >dx[id].score+DINS0)) { dx[id].ijmp ++; if (++ij >= MAXJMP) {writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset +=sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] =−ndely[yy];dx[id].jp.x[ij] = xx; dx[id] .score = dely[yy]; } if (xx == len0 && yy <len1) { /* last col  */ if (endgaps) col1[yy] −= ins0+ins1*(len1−yy);if(col1[yy] > smax) { smax = col1[yy]; dmax = id; } } } if (endgaps &&xx < len0) col1[yy−1] −= ins0+ins1*(len0−xx); if (col1[yy−1] > smax) {smax = col1[yy−1]; dmax = id; } tmp = col0; col0 = col1; col1 = tmp; }(void) free((char *)ndely); (void) free((char *)dely); (void) free((char*)col0); (void) free((char *)col1); } /*  *  * print() -- only routinevisible outside this module  *  * static:  * getmat() -- trace back bestpath, count matches: print()  * pr_align() -- print alignment ofdescribed in array p[]: print()  * dumpblock() -- dump a block of lineswith numbers, stars: pr_align()  * nums() -- put out a number line:dumpblock()  * putline() -- put out a line (name, [num], seq, [num]):dumpblock()  * stars() - -put a line of stars: dumpblock()  *stripname() -- strip any path and prefix from a seqname  */ #include“nw.h” #define SPC  3 #define P_LINE 256 /* maximum output line */#define P_SPC  3 /* space between name or num and seq */ extern_day[26][26]; int olen; /* set output line length */ FILE *fx; /* outputfile */ print() print { int lx, ly, firstgap, lastgap;  /* overlap */ if((fx = fopen(ofile, “w”)) == 0) { fprintf(stderr, “ %s: can't write%s\n”, prog, ofile); cleanup(1); } fprintf(fx, “<first sequence: %s(length = %d)\n”, namex[0], len0); fprintf(fx, “<second sequence: %s(length = %d)\n”, namex[1], len1); olen = 60; lx = len0; ly = len1;firstgap = lastgap = 0; if (dmax < len1 − 1) { /* leading gap in x */pp[0].spc = firstgap = len1 − dmax − 1; ly −= pp[0].spc; } else if(dmax > len1 − 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax −(len1 − 1); lx −= pp[1].spc; } if (dmax0 < len0 − 1) { /* trailing gapin x */ lastgap = len0 − dmax0 −1; lx −= lastgap; } else if (dmax0 >len0 − 1) { /* trailing gap in y */ lastgap = dmax0 − (len0 − 1); ly −=lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align(); } /*  * traceback the best path, count matches  */ static getmat(lx, ly, firstgap,lastgap) getmat int lx, ly; /* “core” (minus endgaps) */ int firstgap,lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1;char outx[32]; double pct; register n0, n1; register char *p0, *p1; /*get total matches, score  */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] +pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 =pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1++; n1++;siz0−−; } else if (siz1) { p0+ +; n0+ +; siz1−−; } else { if(xbm[*p0−‘A’]&xbm[*p1−‘A’]) nm+ +; if (n0++ == pp[0].x[i0]) siz0 =pp[0].n[i0++]; if (nl++ == pp[1].x[i1]) siz1 = pp[1].n[il++]; p0+ +;p1++; } } /* pct homology:  * if penalizing endgaps, base is the shorterseq  * else, knock off overhangs and take shorter core  */ if (endgaps)lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx : ly; pct =100.*(double)nm/(double)lx; fprintf(fx, “\n”); fprintf(fx, “< %d match%sin an overlap of %d: %.2f percent similarity\n”, nm, (nm == 1)? “” :“es”, lx, pct); fprintf(fx, “, gaps in first sequence: %d”, gapx); if(gapx) { (void) sprintf(outx, “ (%d %s%s)”, ngapx, (dna)? “base”:“residue”, (ngapx == 1)? “”:“s”); fprintf(fr, “% s”, outx); fprintf(fx,“, gaps in second sequence: %d”, gapy); if (gapy) { (void) sprintf(outx,“(%d %s%s)”, ngapy, (dna)? “base”:“residue”, (ngapy == 1)? “”:“s”);fprintf(fx, “%s”, outx); } if (dna) fprintf(fx, “\n<score: %d (match =%d, mismatch = %d, gap penalty = %d + %d per base)\n”, smax, DMAT, DMIS,DINS0, DINS1); else fprintf(fx, “\n< score: %d (Dayhoff PAM 250 matrix,gap penalty = %d + %d per residue)\n”, smax, PINS0, PINS1); if (endgaps)fprintf(fx, “<endgaps penalized. left endgap: %d %s%s, right endgap: %d%s%s\n”, firstgap, (dna)? “base” : “residue”, (firstgap == 1)? “” : “s”,lastgap, (dna)? “base” : “residue”, (lastgap == 1)? “” : “s”); elsefprintf(fx, “<endgaps not penalized\n”); } static nm; /* matches in core-- for checking */ static lmax; /* lengths of stripped file names */static ij[2]; /* jmp index for a path */ static nc[2]; /* number atstart of current line */ static ni[2]; /* current elem number -- forgapping */ static siz[2]; static char *ps[2]; /* ptr to current element*/ static char *po[2]; /* ptr to next output char slot */ static charout[2][P_LINE]; /* output line */ static char star[P_LINE]; /* set bystars() */ /*  * print alignment of described in struct path pp[]  */static pr_align() pr_align { int nn; /* char count */ int more; registeri; for (i = 0, lmax = 0; i < 2++) { nn = stripname(namex[i]); if (nn >lmax) lmax = nn; nc[i] = 1; ni[i] = 1; siz[i] = ij[i] = 0; ps[i] =seqx[i]; po[i] = out[i]; } for (nn = nm = 0, more = 1; more;) { for (i =more = 0; i < 2; i++) { /*  * do we have more of this sequence?  */ if(!*ps[i]) continue; more ++; if (pp[i].spc) { /* leading space */*po[i]++ = ‘ ’; pp[i] .spc−−; } else if (siz[i]) { /* in a gap */*po[i]++ = ‘−’; siz[i]−−; } else { /* we're putting a seq element */*po[i] = *ps[i]; if (islower(*ps[i])) *ps[i] = toupper(*ps[i]); po[i]++;ps[i]++; /*  * are we at next gap for this seq?  */ if (ni[i] ==pp[i].x[ij[i]]) { /*  * we need to merge all gaps  * at this location */ siz[i] == pp[i].n[ij[i]++]; while (ni[i] == pp[i].x[ij[i]]) siz[i]+= pp[i].n[ij[i] + +]; } ni[i] + +; } } if (++nn == olen || !more && nn){ dumpblock(); for (i = 0; i < 2; i++) po[i] = out[i]; nn = 0; } } } /* * dump a block of lines, including numbers, stars: pr_align()  */static dumpblock() dumpblock { register i; for(i = 0; i < 2; i++)*po[i]−− = ‘\0’; (void) putc(‘\n’, fx); for (i = 0; i < 2; i++) { if(*out [i] && (*out[i] != ‘ ’ || *(po[i]) != ‘ ’)) { if (i == 0) nums(i);if (i == 0 && *out[1]) stars(); putline(i); if (i == 0 && *out[1])fprintf(fx, star); if (i == 1) nums(i); } } } /* * put out a numberline: dumpblock()  */ static nums(ix) nums int  ix; /* index in out[]holding seq line */ { char nline[P_LINE]; register i, j; register char*pn, *px, *py; for(pn = nline, i = 0; i < lmax+P_SPC; i++, pn++) *pn = ‘’; for (i = nc[ix], py = out[ix]; *py; py++, pn++) { if (*py == ‘ ’ ||*py == ‘−’); *pn = ‘ ’; else { if (i%10 == 0 || (i == 1 && nc[ix] != 1)){ j = (i < 0)? −i ; i; for (px = pn; j; j/= 10, px−−) *px = j%10 + ‘0’;if (i < 0) *px = ‘−’; } else *pn = ‘ ’; i+ +; } } *pn = ‘\0’; nc[ix] =i; for (pn = nline; *pn; pn+ +) (void) putc(*pn, fx); (void) putc(‘\n’,fx); } /*  * put out a line (name, [num], seq. [num]): dumpblock()  */static putline(ix) putline int   ix; { int i; register char *px; for (px= namex[ix], i = 0; *px && *px != ‘:’; px++, i++) (void) putc(*px, fx);for (;i < lmax + P_SPC; i++) (void) putc(‘ ’, fx); /* these count from1:  * ni[] is current element (from 1)  * nc[] is number at start ofcurrent line  */ for (px = out[ix]; *px; px+ +) (void) putc(*px&0x7F,fx); (void) putc(‘\n’, fx); } /*  * put a line of stars (seqs always inout[0], out[1]): dumpblock()  */ static stars() stars { int i; registerchar *p0, *p1, cx, *px; if (!*out[0] || (*out[0] == ‘ ’ && *(p0[0]) == ‘’) || !*out[1] || (*out [1] == ‘ ’ && *(po[1]) == ‘ ’)) return; px =star; for (i = lmax + P_ SPC; i; i−−) *px++ = ‘ ’; for (p0 = out[0], p1= out[1]; *p0 && *p1; p0++, p1++) { if (isalpha(*p0) && isalpha(*p1)) {if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) { cx = ‘*’; nm+ +; } else if (!dna &&_day[*p0− ‘A’][*p1−‘A’] > 0) cx = ‘.’; else cx = ‘ ’; } else cx = ‘ ’;*px++ = cx; } *px++ = ‘\n’; *px = ‘\0’; } /*  * strip path or prefixfrom pn, return len: pr_align()  */ static stripname(pn) stripname char*pn; /* file name (may be path) */ { register char *px, *py; py = 0; for(px = pn; *px; px++) if (*px == ‘/’) py = px + 1; if (py) (void)strcpy(pn, py); return(strlen(pn)); } /*  * cleanup() -- cleanup any tmpfile  * getseq() -- read in seq, set dna, len, maxlen  * g_calloc() --calloc() with error checkin  * readjmps() -- get the good jmps, from tmpfile if necessary  * writejmps() -- write a filled array of jmps to atmp file: nw()  */ #include “nw.h” #include <sys/file.h> char *jname =“/tmp/homgXXXXXX”; /* tmp file for jmps */ FILE *fj; int cleanup(); /*cleanup tmp file */ long lseek(); /*  * remove any tmp file if we blow */ cleanup(i) cleanup int i; { if (fj) (void) unlink(jname); exit(i); }/*  * read, return ptr to seq, set dna, len, maxlen  * skip linesstarting with ‘;’, ‘<’, or ‘>’  * seq in upper or lower case  */ char *getseq(file, len) getseq char *file; /* file name */ int *len; /* seqlen */ { char line[1024], *pseq; register char *px, *py; int natgc,tlen; FILE *fp; if ((fp = fopen(file, “r”)) == 0) { fprintf(stderr, “%s:can't read %s\n”, prog, file); exit(1); } tlen = natgc = 0; while(fgets(line, 1024, fp)) { if (*line == ‘;’ || *line == ‘<’ || *line ==‘>’) continue; for (px = line; *px != ‘\n’; px+ +) if (isupper(*px) ||islower(*px)) tlen++; } if ((pseq = malloc((unsigned)(tlen+ 6))) == 0) {fprintf(stderr, “%s: malloc() failed to get %d bytes for %s\n”, prog,tlen+6, file); exit(1); } pseq[0] = pseq[1] = pseq[2] = pseq[3] = ‘\0’;py = pseq + 4; *len = tlen; rewind(fp); while (fgets(line, 1024, fp)) {if (*line == ‘;’ || *line == ‘<’ || *line == ‘>’) continue; for (px =line; *px != ‘\n’; px++) { if (isupper(*px)) *py++ = *px; else if(islower(*px)) *py+ + = toupper(*px); if (index(“ATGCU” , *(py−1)))natgc+ +; } } *py++ = ‘\0’; *py = ‘\0’; (void) fclose(fp); dna = natgc >(tlen/3); return(pseq+4); } char * g_calloc(msg, nx, sz) g_calloc char*msg; /* program, calling routine */ int nx, sz; /* number and size ofelements */ { char *px, *calloc(); if ((px = calloc((unsigned)nx,(unsigned)sz)) == 0) { if (*msg) { fprintf(stderr, “%s: g_calloc()failed %s (n= %d, sz= %d)\n”, prog, msg, nx, sz); exit(1); } }return(px); } /*  * get final jmps from dx[] or tmp file, set pp[],reset dmax: main()  */ readjmps() readjmps { int fd = −1; int siz, i0,i1; register i, j, xx; if (fj) { (void) fclose(fj); if ((fd =open(jname, O_RDONLY, 0)) < 0) { fprintf(stderr, “%s: can't open()%s\n”, prog, jname); cleanup(1); } } for (i = i0 = i1 = 0, dmax0 = dmax,xx = len0; ;i++) { while (1) { for (j = dx[dmax].ijmp; j >= 0 &&dx[dmax].jp.x[j] >= xx; j−−) if (j < 0 && dx[dmax].offset && fj) {(void) lseek(fd, dx[dmax].offset, 0); (void) read(fd, (char*)&dx[dmax].jp, sizeof(struct jmp)); (void) read(fd, (char*)&dx[dmax].offset, sizeof(dx[dmax].offset)); dx[dmax].ijmp = MAXJMP−1;} else break; } if (i > = JMPS) { fprintf(stderr, “%s: too many gaps inalignment\n”, prog); cleanup(1); } if (j >= 0) { siz = dx[dmax].jp.n[j];xx = dx[dmax].jp.x[j]; dmax += siz; if (siz < 0) { /* gap in second seq*/ pp[1].n[il] = −siz; xx += siz; /* id = xx − yy + len1 − 1  */pp[1].x[il] = xx − dmax + len1 − 1; gapy+ +; ngapy −= siz; /* ignoreMAXGAP when doing endgaps */ siz = (−siz < MAXGAP || endgaps)? −siz :MAXGAP; il++; } else if (siz > 0) { /* gap in first seq */ pp[0] .n[i0]= siz; pp[0] .x[i0] = xx; gapx+ +; ngapx += siz; /* ignore MAXGAP whendoing endgaps */ siz = (siz < MAXGAP || endgaps)? siz : MAXGAP; i0+ +; }} else break; } /* reverse the order of jmps  */ for (j = 0, i0−−; j <i0; j++, i0−−) { i = pp[0].n[j]; pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] =i; i = pp[0].x[j]; pp[0].x[j] = pp[0].x[i0]; pp[0].x[i0] = i; } for (j =0, i1−−;j < i1; j++, i1−−) { i = pp[1].n[j]; pp[1].n[j] = pp[1].n[i1];pp[1].n[i1] = i; i = pp[1].x[j]; pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] =i; } if (fd > = 0) (void) close(fd); if (fj) { (void) unlink(jname); fj= 0; offset = 0; } } /*  * write a filled jmp struct offset of the prevone (if any): nw()  */ writejmps(ix) writejmps int ix; { char *mktemp();if (!fj) { if (mktemp(jname) < 0) { fprintf(stderr, “%s: can't mktemp()%s\n”, prog, jname); cleanup(1); } if ((fj = fopen(jname, “w”) == 0) {fprintf(stderr, “%s: can't write %s\n”, prog, jname); exit(1); } }(void) fwrite((char *)&dx[ix].jp, sizeof( struct jmp), 1, fj); (void)fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) ComparisonXXXXXYYYYYYY (Length = 12 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) =acid residues of the PRO polypeptide) = 5 divided by 15 = 33.3%

TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) = 5divided by 10 = 50%

TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) ComparisonNNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA % nucleic acid sequenceidentity = (the number of identically matching nucleotides between thetwo nucleic acid sequences as determined by ALIGN-2) divided by (thetotal number of nucleotides of the PRO-DNA nucleic acid sequence) = 6divided by 14 = 42.9%

TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNANNNNLLLVV (Length = 9 nucleotides) % nucleic acid sequence identity =(the number of identically matching nucleotides between the two nucleicacid sequences as determined by ALIGN-2) divided by (the total number ofnucleotides of the PRO-DNA nucleic acid sequence) = 4 divided by 12 =33.3%

II. Compositions and Methods of the Invention

A. Full-Length PRO Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO polypeptides. In particular, cDNAs encoding various PROpolypeptides have been identified and isolated, as disclosed in furtherdetail in the Examples below. It is noted that proteins produced inseparate expression rounds may be given different PRO numbers but theUNQ number is unique for any given DNA and the encoded protein, and willnot be changed. However, for sake of simplicity, in the presentspecification the protein encoded by the full length native nucleic acidmolecules disclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will be referredto as “PRO/number”, regardless of their origin or mode of preparation.

As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in, the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the PRO polypeptides and encoding nucleic acidsdescribed herein, Applicants have identified what is believed to be thereading frame best identifiable with the sequence information availableat the time.

1. Full-length PRO211 and PRO217 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO211 and PRO217. In particular, Applicants have identified andisolated cDNA encoding PRO211 and PRO217 polypeptides, as disclosed infurther detail in the Examples below. Using BLAST (FastA format)sequence alignment computer programs, Applicants found that cDNAsequences encoding full-length native sequence PRO211 and PRO217 havehomologies to known proteins having EGF-like domains. Specifically, thecDNA sequence DNA32292-1131 (FIG. 1, SEQ ID NO:1) has certain identifyand a Blast score of 209 with PAC6_RAT and certain identify and a Blastscore of 206 with Fibulin-1, isoform c precursor. The cDNA sequenceDNA33094-1131 (FIG. 3, SEQ ID NO:3) has 36% identity and a Blast scoreof 336 with eastern newt tenascin, and 37% identity and a Blast score of331 with human tenascin-X precursor. Accordingly, it is presentlybelieved that PRO211 and PRO217 polypeptides disclosed in the presentapplication are newly identified members of the EGF-like family andpossesses properties typical of the EGF-like protein family.

2. Full-length PRO230 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO230. In particular, Applicants have identified and isolated cDNAencoding a PRO230 polypeptide, as disclosed in further detail in theExamples below. Using known programs such as BLAST and FastA sequencealignment computer programs, Applicants found that a cDNA sequenceencoding full-length native sequence PRO230 has 48% amino acid identitywith the rabbit tubulointerstitial nephritis antigen precursor.Accordingly, it is presently believed that PRO230 polypeptide disclosedin the present application is a newly identified member of thetubulointerstitial nephritis antigen family and possesses the ability tobe recognized by human autoantibodies in certain forms oftubulointerstitial nephritis.

3. Full-length PRO232 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO232. In particular, Applicants have identified and isolated cDNAencoding a PRO232 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the full-length nativesequence PRO232 (shown in FIG. 9 and SEQ ID NO:18) has 35% sequenceidentity with a stem cell surface antigen from Gallus gallus.Accordingly, it is presently believed that the PRO232 polypeptidedisclosed in the present application may be a newly identified stem cellantigen.

4. Full-length PRO187 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO187. In particular, Applicants have identified and isolated cDNAencoding a PRO187 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO187(shown in FIG. 15) has 74% amino acid sequence identity and BLAST scoreof 310 with various androgen-induced growth factors and FGF-8.Accordingly, it is presently believed that PRO187 polypeptide disclosedin the present application is a newly identified member of the FGF-8protein family and may possess identify activity or property typical ofthe FGF-8-like protein family.

5. Full-length PRO265 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO265. In particular, Applicants have identified and isolated cDNAencoding a PRO265 polypeptide, as disclosed in further detail in theExamples below. Using programs such as BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO265 polypeptide have significant homology with the fibromodulinprotein and fibromodulin precursor protein. Applicants have also foundthat the DNA encoding the PRO265 polypeptide has significant homologywith platelet glycoprotein V, a member of the leucine rich relatedprotein family involved in skin and wound repair. Accordingly, it ispresently believed that PRO265 polypeptide disclosed in the presentapplication is a newly identified member of the leucine rich repeatfamily and possesses protein protein binding capabilities, as well as beinvolved in skin and wound repair as typical of this family.

6. Full-length PRO219 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO219. In particular, Applicants have identified and isolated cDNAencoding a PRO219 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO219polypeptide have significant homology with the mouse and humanmatrilin-2 precursor polypeptides. Accordingly, it is presently believedthat PRO219 polypeptide disclosed in the present application is relatedto the matrilin-2 precursor polypeptide.

7. Full-length PRO246 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO246. In particular, Applicants have identified and isolated cDNAencoding a PRO246 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the PRO246 polypeptide hassignificant homology with the human cell surface protein HCAR.Accordingly, it is presently believed that PRO246 polypeptide disclosedin the present application may be a newly identified membrane-boundvirus receptor or tumor cell-specific antigen.

8. Full-length PRO228 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO228. In particular, Applicants have identified and isolated cDNAencoding a PRO228 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO228polypeptide have significant homology with the EMR1 protein. Applicantshave also found that the DNA encoding the PRO228 polypeptide hassignificant homology with latrophilin, macrophage-restricted cellsurface glycoprotein, B0457.1 and leucocyte antigen CD97 precursor.Accordingly, it is presently believed that PRO228 polypeptide disclosedin the present application is a newly identified member of the seventransmembrane superfamily and possesses characteristics and functionalproperties typical of this family. In particular, it is believed thatPRO228 is a new member of the subgroup within this family to which CD97and EMR1 belong.

9. Full-length PRO533 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO533. In particular, Applicants have identified and isolated cDNAencoding a PRO533 polypeptide, as disclosed in further detail in theExamples below. Using BLAST-2 and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO533(shown in FIG. 22 and SEQ ID NO:59) has a Blast score of 509 and 53%amino acid sequence identity with fibroblast growth factor (FGF).Accordingly, it is presently believed that PRO533 disclosed in thepresent application is a newly identified member of the fibroblastgrowth factor family and may possess activity typical of suchpolypeptides.

10. Full-length PRO245 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO245. In particular, Applicants have identified and isolated cDNAencoding a PRO245 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the amino acid sequence ofthe PRO245 polypeptide has 60% amino acid identity with the human c-mybprotein. Accordingly, it is presently believed that the PRO245polypeptide disclosed in the present application may be a newlyidentified member of the transmembrane protein tyrosine kinase family.

11. Full-length PRO220, PRO221 and PRO227 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO220, PRO221 and PRO227. In particular, Applicants have identifiedand isolated cDNAs encoding a PRO220, PRO221 and PRO227 polypeptide,respectively, as disclosed in further detail in the Examples below.Using BLAST and FastA sequence alignment computer programs, PRO220 hasamino acid identity with the amino acid sequence of a leucine richprotein wherein the identity is 87%. PRO220 additionally has amino acididentity with the neuronal leucine rich protein wherein the identity is55%. The neuronal leucine rich protein is further described in Taguchi,et al., Mol. Brain Res., 35:31-40 (1996).

PRO221 has amino acid identity with the SLIT protein precursor, whereindifferent portions of these two proteins have the respective percentidentities of 39%, 38%, 34%, 31%, and 30%.

PRO227 has amino acid identity with the amino acid sequence of plateletglycoprotein V precursor. The same results were obtained for humanglycoprotein V. Different portions of these two proteins show thefollowing percent identities of 30%, 28%, 28%, 31%, 35%, 39% and 27%.

Accordingly, it is presently believed that PRO220, PRO221 and PRO227polypeptides disclosed in the present application are newly identifiedmembers of the leucine rich repeat protein superfamily and that eachpossesses protein—protein binding capabilities typical of the leucinerich repeat protein superfamily. It is also believed that they havecapabilities similar to those of SLIT, the leucine rich repeat proteinand human glycoprotein V.

12. Full-length PRO258 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO258. In particular, Applicants have identified and isolated cDNAencoding a PRO258 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO258polypeptide have significant homology with the CRTAM and poliovirusreceptors. Accordingly, it is presently believed that PRO258 polypeptidedisclosed in the present application is a newly identified member of theIg superfamily and possesses virus receptor capabilities or regulatesimmune function as typical of this family.

13. Full-length PRO266 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO266. In particular, Applicants have identified and isolated cDNAencoding a PRO266 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO266polypeptide have significant homology with the SLIT protein fromDrosophilia. Accordingly, it is presently believed that PRO266polypeptide disclosed in the present application is a newly identifiedmember of the leucine rich repeat family and possesses ligand—ligandbinding activity and neuronal development typical of this family. SLIThas been shown to be useful in the study and treatment of Alzheimer'sdisease, supra, and thus, PRO266 may have involvement in the study andcure of this disease.

14. Full-length PRO269 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO269. In particular, Applicants have identified and isolated cDNAencoding a PRO269 polypeptide, as disclosed in further detail in theExamples below. Using BLAST, FastA and sequence alignment computerprograms, Applicants found that the amino acid sequence encoded bynucleotides 314 to 1783 of the full-length native sequence PRO269 (shownin FIG. 35 and SEQ ID NO:95) has significant homology to human urinarythrombomodulin and various thrombomodulin analogues respectively, towhich it was aligned. Accordingly, it is presently believed that PRO269polypeptide disclosed in the present application is a newly identifiedmember of the thrombomodulin family.

15. Full-length PRO287 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO287. In particular, Applicants have identified and isolated cDNAencoding a PRO287 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO287polypeptide have significant homology with the type 1 procollagenC-proteinase enhancer protein precursor and type 1 procollagenC-proteinase enhancer protein. Accordingly, it is presently believedthat PRO287 polypeptide disclosed in the present application is a newlyidentified member of the C-proteinase enhancer protein family.

16. Full-length PRO214 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO214. In particular, Applicants have identified and isolated cDNAencoding a PRO214 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO214polypeptide (shown in FIG. 40 and SEQ ID NO:109) has 49% amino acidsequence identity with HT protein, a known member of the EGF-family. Thecomparison resulted in a BLAST score of 920, with 150 matchingnucleotides. Accordingly, it is presently believed that the PRO214polypeptide disclosed in the present application is a newly identifiedmember of the family comprising EGF domains and may possess activitiesor properties typical of the EGF-domain containing family.

17. Full-length PRO317 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO317. In particular, cDNA encoding a PRO317 polypeptide has beenidentified and isolated, as disclosed in further detail in the Examplesbelow. Using BLAST™ and FastA™ sequence alignment computer programs, itwas found that a full-length native-sequence PRO317 (shown in FIG. 42and SEQ ID NO:114) has 92% amino acid sequence identity with EBAF-1.Further, it is closely aligned with many other members of the TGF-superfamily.

Accordingly, it is presently believed that PRO317 disclosed in thepresent application is a newly identified member of the TGF- superfamilyand may possess properties that are therapeutically useful in conditionsof uterine bleeding, etc. Hence, PRO317 may be useful in diagnosing ortreating abnormal bleeding involved in gynecological diseases, forexample, to avoid or lessen the need for a hysterectomy. PRO317 may alsobe useful as an agent that affects angiogenesis in general, so PRO317may be useful in anti-tumor indications, or conversely, in treatingcoronary ischemic conditions.

Library sources reveal that ESTs used to obtain the consensus DNA forgenerating PRO317 primers and probes were found in normal tissues(uterus, prostate, colon, and pancreas), in several tumors (colon, brain(twice), pancreas, and mullerian cell), and in a heart with ischemia.PRO317 has shown up in several tissues as well, but it does look to havea greater concentration in uterus. Hence, PRO317 may have a broader useby the body than EBAF-1. It is contemplated that, at least for someindications, PRO317 may have opposite effects from EBAF-1.

18. Full-length PRO301 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO301. In particular, Applicants have identified and isolated cDNAencoding a PRO301 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO301(shown in FIG. 44 and SEQ ID NO:119) has a Blast score of 246corresponding to 30% amino acid sequence identity with human A33 antigenprecursor. Accordingly, it is presently believed that PRO301 disclosedin the present application is a newly identified member of the A33antigen protein family and may be expressed in human neoplastic diseasessuch as colorectal cancer.

19. Full-length PRO224 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO224. In particular, Applicants have identified and isolated cDNAencoding a PRO224 polypeptide, as disclosed in further detail in theExamples below. Using known programs such as BLAST and FastA sequencealignment computer programs, Applicants found that full-length nativePRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity withapolipoprotein E receptor 2906 from homo sapiens. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 37%, 36%, 30%, 44%, 44% and 28% respectively. Full-length nativePRO224 (FIG. 46, SEQ ID NO:127) also has amino acid identity with verylow-density lipoprotein receptor precursor from gall. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 38%, 37%, 42%, 33%, and 37% respectively. Additionally, full-lengthnative PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with thechicken oocyte receptor P95 from Gallus gallus. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 38%, 37%,42%, 33%, and 37% respectively. Moreover, full-length nativePRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with very lowdensity lipoprotein receptor short form precursor from humans. Thealignments of different portions of these two polypeptides show aminoacid identities of 32%, 38%, 34%, 45%, and 31%, respectively.Accordingly, it is presently believed that PRO224 polypeptide disclosedin the present application is a newly identified member of the lowdensity lipoprotein receptor family and possesses the structuralcharacteristics required to have the functional ability to recognize andendocytose low density lipoproteins typical of the low densitylipoprotein receptor family. (The alignments described above used thefollowing scoring parameters: T=7, S+65, S2=36, Matrix: BLOSUM62.)

20. Full-length PRO222 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO222. In particular, Applicants have identified and isolated cDNAencoding a PRO222 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a sequence encoding full-length nativesequence PRO222 (shown in FIG. 48 and SEQ ID NO:132) has 25-26% aminoacid identity with mouse complement factor h precursor, has 27-29% aminoacid identity with complement receptor, has 25-47% amino acid identitywith mouse complement C3b receptor type 2 long form precursor, has 40%amino acid identity with human hypothetical protein kiaa0247.Accordingly, it is presently believed that PRO222 polypeptide disclosedin the present application is a newly identified member of thecomplement receptor family and possesses activity typical of thecomplement receptor family.

21. Full-length PRO234 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO234. In particular, Applicants have identified and isolated cDNAencoding a PRO234 polypeptide, as disclosed in further detail in theExamples below. Using BLAST (FastA-fornat) sequence alignment computerprograms, Applicants found that a cDNA sequence encoding full-lengthnative sequence PRO234 has 31% identity and Blast score of 134 withE-selectin precursor. Accordingly, it is presently believed that thePRO234 polypeptides disclosed in the present application are newlyidentified members of the lectin/selectin family and possess activitytypical of the lectin/selectin family.

22. Full-length PRO231 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO231. In particular, Applicants have identified and isolated cDNAencoding a PRO231 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the full-length native sequence PRO231polypeptide (shown in FIG. 52 and SEQ ID NO:142) has 30% and 31% aminoacid identity with human and rat prostatic acid phosphatase precursorproteins, respectively. Accordingly, it is presently believed that thePRO231 polypeptide disclosed in the present application may be a newlyidentified member of the acid phosphatase protein family.

23. Full-length PRO229 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO229. In particular, Applicants have identified and isolated cDNAencoding a PRO229 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO229polypeptide have significant homology with antigen wc1.1, M130 antigen,T cell surface glycoprotein CD6 and CD6. It also is related to Sp-alpha.Accordingly, it is presently believed that PRO229 polypeptide disclosedin the present application is a newly identified member of the familycontaining scavenger receptor homology, a sequence motif found in anumber of proteins involved in immune function and thus possesses immunefunction and/or segments which resist degradation, typical of thisfamily.

24. Full-length PRO238 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO238. In particular, Applicants have identified and isolated cDNAencoding a PRO238 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO238polypeptide have significant homology with reductases, includingoxidoreductase and fatty acyl-CoA reductase. Accordingly, it ispresently believed that PRO238 polypeptide disclosed in the presentapplication is a newly identified member of the reductase family andpossesses reducing activity typical of the reductase family.

25. Full-length PRO233 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO233. In particular, Applicants have identified and isolated cDNAencoding a PRO233 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO233polypeptide have significant homology with the reductase protein.Applicants have also found that the DNA encoding the PRO233 polypeptidehas significant homology with proteins from Caenorhabditis elegans.Accordingly, it is presently believed that PRO233 polypeptide disclosedin the present application is a newly identified member of the reductasefamily and possesses the ability to effect the redox state of the celltypical of the reductase family.

26. Full-length PRO223 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO223. In particular, Applicants have identified and isolated cDNAencoding a PRO223 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the PRO223 polypeptide has significanthomology with various serine carboxypeptidase polypeptides. Accordingly,it is presently believed that PRO223 polypeptide disclosed in thepresent application is a newly identified serine carboxypeptidase.

27. Full-length PRO235 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO235. In particular, Applicants have identified and isolated cDNAencoding a PRO235 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO235polypeptide have significant homology with the various plexin proteins.Accordingly, it is presently believed that PRO235 polypeptide disclosedin the present application is a newly identified member of the plexinfamily and possesses cell adhesion properties typical of the plexinfamily.

28. Full-length PRO236 and PRO262 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO236 and PRO262. In particular, Applicants have identified andisolated cDNA encoding PRO236 and PRO262 polypeptides, as disclosed infurther detail in the Examples below. Using BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO236 and PRO262 polypeptides have significant homology withvarious β-galactosidase and β-galactosidase precursor polypeptides.Accordingly, it is presently believed that the PRO236 and PRO262polypeptides disclosed in the present application are newly identifiedβ-galactosidase homologs.

29. Full-length PRO239 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO239. In particular, Applicants have identified and isolated cDNAencoding a PRO239 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO239polypeptide have significant homology with densin proteins. Accordingly,it is presently believed that PRO239 polypeptide disclosed in thepresent application is a newly identified member of the densin familyand possesses cell adhesion and the ability to effect synaptic processesas is typical of the densin family.

30. Full-length PRO257 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO257. In particular, Applicants have identified and isolated cDNAencoding a PRO257 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO257polypeptide have significant homology with the ebnerin precursor andebnerin protein. Accordingly, it is presently believed that PRO257polypeptide disclosed in the present application is a newly identifiedprotein member which is related to the ebnerin protein.

31. Full-length PRO260 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO260. In particular, Applicants have identified and isolated cDNAencoding a PRO260 polypeptide, as disclosed in further detail in theExamples below. Using programs such as BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO260 polypeptide have significant homology with thealpha-l-fucosidase precursor. Accordingly, it is presently believed thatPRO260 polypeptide disclosed in the present application is a newlyidentified member of the fucosidase family and possesses enzymaticactivity related to fucose residues typical of the fucosidase family.

32. Full-length PRO263 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO263. In particular, Applicants have identified and isolated cDNAencoding a PRO263 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO263polypeptide have significant homology with the CD44 antigen and relatedproteins. Accordingly, it is presently believed that PRO263 polypeptidedisclosed in the present application is a newly identified member of theCD44 antigen family and possesses at least one of the propertiesassociated with these antigens, i.e., cancer and HIV marker, cell—cellor cell-matrix interactions, regulating cell traffic, lymph node homing,transmission of growth signals, and presentation of chemokines andgrowth facors to traveling cells.

33. Full-length PRO270Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO270. In particular, Applicants have identified and isolated cDNAencoding a PRO270 polypeptide, as disclosed in further detail in theExamples below. Using BLAST, FastA and sequence alignment computerprograms, Applicants found that that various portions of the PRO270polypeptide have significant homology with various thioredoxin proteins.Accordingly, it is presently believed that PRO270 polypeptide disclosedin the present application is a newly identified member of thethioredoxin family and possesses the ability to effectreduction-oxidation (redox) state typical of the thioredoxin family.

34. Full-length PRO271 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO271. In particular, Applicants have identified and isolated cDNAencoding a PRO271 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the PRO271 polypeptide has significanthomology with various link proteins and precursors thereof. Accordingly,it is presently believed that PRO271 polypeptide disclosed in thepresent application is a newly identified link protein homolog.

35. Full-length PRO272 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO272. In particular, Applicants have identified and isolated cDNAencoding a PRO272 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO272polypeptide have significant homology with the human reticulocalbinprotein and its precursors. Applicants have also found that the DNAencoding the PRO272 polypeptide has significant homology with the mousereticulocalbin precursor protein. Accordingly, it is presently believedthat PRO272 polypeptide disclosed in the present application is a newlyidentified member of the reticulocalbin family and possesses the abilityto bind calcium typical of the reticulocalbin family.

36. Full-length PRO294 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO294. In particular, Applicants have identified and isolated cDNAencoding a PRO294 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO294polypeptide have significant homology with the various portions of anumber of collagen proteins. Accordingly, it is presently believed thatPRO294 polypeptide disclosed in the present application is a newlyidentified member of the collagen family.

37. Full-length PRO295 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO295. In particular, Applicants have identified and isolated cDNAencoding a PRO295 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO295polypeptide have significant homology with integrin proteins.Accordingly, it is presently believed that PRO295 polypeptide disclosedin the present application is a newly identified member of the integrinfamily and possesses cell adhesion typical of the integrin family.

38. Full-length PRO293 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO293. In particular, Applicants have identified and isolated cDNAencoding a PRO293 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that portions of the PRO293 polypeptide havesignificant homology with the neuronal leucine rich repeat proteins 1and 2, (NLRR-1 and NLRR-2), particularly NLRR-2. Accordingly, it ispresently believed that PRO293 polypeptide disclosed in the presentapplication is a newly identified member of the neuronal leucine richrepeat protein family and possesses ligand—ligand binding activitytypical of the NRLL protein family.

39. Full-length PRO247 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO247. In particular, Applicants have identified and isolated cDNAencoding a PRO247 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO247polypeptide have significant homology with densin. Applicants have alsofound that the DNA encoding the PRO247 polypeptide has significanthomology with a number of other proteins, including KIAA0231.Accordingly, it is presently believed that PRO247 polypeptide disclosedin the present application is a newly identified member of the leucinerich repeat family and possesses ligand binding abilities typical ofthis family.

40. Full-length PRO302, PRO303, PRO304, PRO307 and PRO343 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO302, PRO303, PRO304, PRO307 and PRO343. In particular, Applicantshave identified and isolated cDNA encoding PRO302, PRO303, PRO304,PRO307 and PRO343 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO302, PRO303,PRO304, PRO307 and PRO343 polypeptides have significant homology withvarious protease proteins. Accordingly, it is presently believed thatthe PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides disclosed inthe present application are newly identified protease proteins.

41. Full-length PRO328 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO328. In particular, Applicants have identified and isolated cDNAencoding a PRO328 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO328polypeptide have significant homology with the human glioblastomaprotein (“GLIP”). Further, Applicants found that various portions of thePRO328 polypeptide have significant homology with the cysteine richsecretory protein (“CRISP”) as identified by BLAST homology[ECCRISP3_(—)1, S68683, and CRS3_HUMAN]. Accordingly, it is presentlybelieved that PRO328 polypeptide disclosed in the present application isa newly identified member of the GLIP or CRISP families and possessestranscriptional regulatory activity typical of the GLIP or CRISPfamilies.

42. Full-length PRO335, PRO331 and PRO326 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO335, PRO331 or PRO326. In particular, Applicants have identifiedand isolated cDNA encoding a PRO335, PRO331 or PRO326 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST and FastAsequence alignment computer programs, Applicants found that variousportions of the PRO335, PRO331 or PRO326 polypeptide have significanthomology with LIG-1, ALS and in the case of PRO331, additionally,decorin. Accordingly, it is presently believed that the PRO335, PRO331and PRO326 polypeptides disclosed in the present application are newlyidentified members of the leucine rich repeat superfamily, andparticularly, are related to LIG-1 and possess the biological functionsof this family as discussed and referenced herein.

43. Full-length PRO332 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO332. In particular, Applicants have identified and isolated cDNAencoding PRO332 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO332(shown in FIG. 108 and SEQ ID NO:310) has about 3040% amino acidsequence identity with a series of known proteoglycan sequences,including, for example, fibromodulin and fibromodulin precursorsequences of various species (FMOD_BOVIN, FMOD_CHICK, FMOD_RAT,FMOD_MOUSE, FMOD_HUMAN, P_R36773), osteomodulin sequences (AB000114₁₃ 1,AB007848_(—)1), decorin sequences (CFU83141_(—)1, OCU03394_(—)1, PR42266, P_R42267, P_R42260, P_R89439), keratan sulfate proteoglycans(BTU48360_(—)1, AF022890_(—)1), corneal proteoglycan (AF022256_(—)1),and bone/cartilage proteoglycans and proteoglycane precursors(PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN). Accordingly, it is presentlybelieved that PRO332 disclosed in the present application is a newproteoglycan-type molecule, and may play a role in regulatingextracellular matrix, cartilage, and/or bone function.

44. Full-length PRO334 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO334. In particular, Applicants have identified and isolated cDNAencoding a PRO334 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO334polypeptide have significant homology with fibulin and fibrillin.Accordingly, it is presently believed that PRO334 polypeptide disclosedin the present application is a newly identified member of the epidermalgrowth factor family and possesses properties and activities typical ofthis family.

45. Full-length PRO346 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO346. In particular, Applicants have identified and isolated cDNAencoding a PRO346 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO346(shown in FIG. 112 and SEQ ID NO:320) has 28% amino acid sequenceidentity with carcinoembryonic antigen. Accordingly, it is presentlybelieved that PRO346 disclosed in the present application is a newlyidentified member of the carcinoembryonic protein family and may beexpressed in association with neoplastic tissue disorders.

46. Full-length PRO268 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO268. In particular, Applicants have identified and isolated cDNAencoding a PRO268 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that portions of the PRO268 polypeptide havesignificant homology with the various protein disulfide isomeraseproteins. Accordingly, it is presently believed that PRO268 polypeptidedisclosed in the present application is a homolog of the proteindisulfide isomerase p5 protein.

47. Full-length PRO330 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO330. In particular, Applicants have identified and isolated cDNAencoding a PRO330 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO330polypeptide have significant homology with the murine prolyl4-hydroxylase alpha-II subunit protein. Accordingly, it is presentlybelieved that PRO330 polypeptide disclosed in the present application isa novel prolyl 4-hydroxylase subunit polypeptide.

48. Full-length PRO339 and PRO310 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO339 and PRO310. In particular, Applicants have identified andisolated cDNA encoding a PRO339 polypeptide, as disclosed in furtherdetail in the Examples below. Applicants have also identified andisolated cDNA encoding a PRO310 polypeptide, as disclosed in furtherdetail in the Examples below. Using BLAST and FastA sequence alignmentcomputer programs, Applicants found that various portions of the PRO339and PRO310 polypeptides have significant homology with small secretedproteins from C. elegans and are distantly related to fringe. PRO339also shows homology to collagen-like polymers. Sequences which were usedto identify PRO310, designated herein as DNA40533 and DNA42267, alsoshow homology to proteins from C. elegans. Accordingly, it is presentlybelieved that the PRO339 and PRO310 polypeptides disclosed in thepresent application are newly identified member of the family ofproteins involved in development, and which may have regulatoryabilities similar to the capability of fringe to regulate serrate.

49. Full Length PRO244 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding C-type lectins referred to in the present applicationas PRO244. In particular, applicants have identified and isolated cDNAencoding PRO244 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO244(shown in FIG. 122 and SEQ ID NO:377) has 43% amino acid sequenceidentity with the hepatic lectin gallus gallus (LECH-CHICK), and 42%amino acid sequence identity with an HIV gp120 binding C-type lectin(A46274). Accordingly, it is presently believed that PRO244 disclosed inthe present application is a newly identified member of the C-lectinsuperfamily and may play a role in immune function, apoptosis, or in thepathogenesis of atherosclerosis. In addition, PRO244 may be useful inidentifying tumor-associated epitopes.

B. PRO Polypeptide Variants

In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can be prepared.PRO variants can be prepared by introducing appropriate nucleotidechanges into the PRO DNA, and/or by synthesis of the desired PROpolypeptide. Those skilled in the art will appreciate that amino acidchanges may alter post-translational processes of the PRO, such aschanging the number or position of glycosylation sites or altering themembrane anchoring characteristics.

Variations in the native full-length sequence PRO or in various domainsof the PRO described herein, can be made, for example, using any of thetechniques and guidelines for conservative and non-conservativemutations set forth, for instance, in U.S. Pat. No. 5,364,934.Variations may be a substitution, deletion or insertion of one or morecodons encoding the PRO that results in a change in the amino acidsequence of the PRO as compared with the native sequence PRO. Optionallythe variation is by substitution of at least one amino acid with anyother amino acid in one or more of the domains of the PRO. Guidance indetermining which amino acid residue may be inserted, substituted ordeleted without adversely affecting the desired activity may be found bycomparing the sequence of the PRO with that of homologous known proteinmolecules and minimizing the number of amino acid sequence changes madein regions of high homology. Amino acid substitutions can be the resultof replacing one amino acid with another amino acid having similarstructural and/or chemical properties, such as the replacement of aleucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

PRO polypeptide fragments are provided herein. Such fragments may betruncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length native protein.Certain fragments lack amino acid residues that are not essential for adesired biological activity of the PRO polypeptide.

PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemically synthesized. Analternative approach involves generating PRO fragments by enzymaticdigestion, e.g., by treating the protein with an enzyme known to cleaveproteins at sites defined by particular amino acid residues, or bydigesting the DNA with suitable restriction enzymes and isolating thedesired fragment. Yet another suitable technique involves isolating andamplifying a DNA fragment encoding a desired polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

In particular embodiments, conservative substitutions of interest areshown in Table 6 under the heading of preferred substitutions. If suchsubstitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened.

TABLE 6 Original Exemplary Preferred Residue Substitutions SubstitutionsAla (A) val; leu; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his;lys; arg gln Asp (D) glu glu Cys (C) ser ser Gln (Q) asn asn Glu (E) aspasp Gly (G) pro; ala ala His (H) asn; gln; lys; arg arg Ile (I) leu;val; met; ala; phe; leu norleucine Leu (L) norleucine; ile; val; ilemet; ala; phe Lys (K) arg; gln; asn arg Met (M) leu; phe; ile leu Phe(F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T)ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile;leu; met; phe; leu ala; norleucine

Substantial modifications in function or immunological identity of thePRO polypeptide are accomplished by selecting substitutions that differsignificantly in their effect on maintaining (a) the structure of thepolypeptide backbone in the area of the substitution, for example, as asheet or helical conformation, (b) the charge or hydrophobicity of themolecule at the target site, or (c) the bulk of the side chain.Naturally occurring residues are divided into groups based on commonside-chain properties:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gln, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another class. Such substituted residues also may beintroduced into the conservative substitution sites or, more preferably,into the remaining (non-conserved) sites.

The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487(1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317:415 (1986)] or other known techniques can be performedon the cloned DNA to produce the PRO variant DNA.

Scanning amino acid analysis can also be employed to identify one ormore amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244:1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins,(W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

C. Modifications of PRO

Covalent modifications of PRO are included within the scope of thisinvention. One type of covalent modification includes reacting targetedamino acid residues of a PRO polypeptide with an organic derivatizingagent that is capable of reacting with selected side chains or the N- orC-terminal residues of the PRO. Derivatization with bifunctional agentsis useful, for instance, for crosslinking PRO to a water-insolublesupport matrix or surface for use in the method for purifying anti-PROantibodies, and vice-versa. Commonly used crosslinking agents include,e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylicacid, homobifunctional imidoesters, including disuccinimidyl esters suchas 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides suchas bis-N-maleimido-1,8-octane and agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl and asparaginylresidues to the corresponding glutamyl and aspartyl residues,respectively, hydroxylation of proline and lysine, phosphorylation ofhydroxyl groups of seryl or threonyl residues, methylation of theα-amino groups of lysine, arginine, and histidine side chains [T. E.Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman &Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminalamine, and amidation of any C-terminal carboxyl group.

Another type of covalent modification of the PRO polypeptide includedwithin the scope of this invention comprises altering the nativeglycosylation pattern of the polypeptide. “Altering the nativeglycosylation pattern” is intended for purposes herein to mean deletingone or more carbohydrate moieties found in native sequence PRO (eitherby removing the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequencePRO. In addition, the phrase includes qualitative changes in theglycosylation of the native proteins, involving a change in the natureand proportions of the various carbohydrate moieties present.

Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alteration may bemade, for example, by the addition of, or substitution by, one or moreserine or threonine residues to the native sequence PRO (for O-inkedglycosylation sites). The PRO amino acid sequence may optionally bealtered through changes at the DNA level, particularly by mutating theDNA encoding the PRO polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on thePRO polypeptide is by chemical or enzymatic coupling of glycosides tothe polypeptide. Such methods are described in the art, e.g., in WO87/05330 published Sep. 11, 1987, and in Aplin and Wriston, CRC Crit.Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on the PRO polypeptide may beaccomplished chemically or enzymatically or by mutational substitutionof codons encoding for amino acid residues that serve as targets forglycosylation. Chemical deglycosylation techniques are known in the artand described, for instance, by Hakimuddin, et al., Arch. Biochem.Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131(1981). Enzymatic cleavage of carbohydrate moieties on polypeptides canbe achieved by the use of a variety of endo- and exo-glycosidases asdescribed by Thotakura et al., Meth. Enzymol., 138:350 (1987).

Another type of covalent modification of PRO comprises linking the PROpolypeptide to one of a variety of nonproteinaceous polymers, e.g.,polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, inthe manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144;4,670,417; 4,791,192 or 4,179,337.

The PRO of the present invention may also be modified in a way to form achimeric molecule comprising PRO fused to another, heterologouspolypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion of thePRO with a tag polypeptide which provides an epitope to which ananti-tag antibody can selectively bind. The epitope tag is generallyplaced at the amino- or carboxyl-terminus of the PRO. The presence ofsuch epitope-tagged forms of the PRO can be detected using an antibodyagainst the tag polypeptide. Also, provision of the epitope tag enablesthe PRO to be readily purified by affinity purification using ananti-tag antibody or another type of affinity matrix that binds to theepitope tag. Various tag polypeptides and their respective antibodiesare well known in the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165(1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10antibodies thereto [Evan et al., Molecular and Cellular Biology,5:3610-3616 (1985]; and the Herpes Simplex virus glycoprotein D (gD) tagand its antibody [Paborsky et al., Protein Engineering, 3(6):547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al.,BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin etal., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinneret al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA,87:6393-6397 (1990)].

In an alternative embodiment, the chimeric molecule may comprise afusion of the PRO with an immunoglobulin or a particular region of animmunoglobulin. For a bivalent form of the chimeric molecule (alsoreferred to as an “immunoadhesin”), such a fusion could be to the Fcregion of an IgG molecule. The Ig fusions preferably include thesubstitution of a soluble (transmembrane domain deleted or inactivated)form of a PRO polypeptide in place of at least one variable regionwithin an Ig molecule. In a particularly preferred embodiment, theimmunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge,CH1, CH2 and CH3 regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

D. Preparation of PRO

The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containing PROnucleic acid. It is, of course, contemplated that alternative methods,which are well known in the art, may be employed to prepare PRO. Forinstance, the PRO sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined using chemicalor enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

DNA encoding PRO may be obtained from a cDNA library prepared fromtissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also be obtainedfrom a genomic library or by known synthetic procedures (e.g., automatednucleic acid synthesis).

Libraries can be screened with probes (such as antibodies to the PRO oroligonucleotides of at least about 20-80 bases) designed to identify thegene of interest or the protein encoded by it. Screening the cDNA orgenomic library with the selected probe may be conducted using standardprocedures, such as described in Sambrook et al., Molecular Cloning: ALaboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).An alternative means to isolate the gene encoding PRO is to use PCRmethodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: ALaboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

The Examples below describe techniques for screening a cDNA library. Theoligonucleotide sequences selected as probes should be of sufficientlength and sufficiently unambiguous that false positives are minimized.The oligonucleotide is preferably labeled such that it can be detectedupon hybridization to DNA in the library being screened. Methods oflabeling are well known in the art, and include the use of radiolabelslike ³²P-labeled ATP, biotinylation or enzyme labeling. Hybridizationconditions, including moderate stringency and high stringency, areprovided in Sambrook et al., supra.

Sequences identified in such library screening methods can be comparedand aligned to other known sequences deposited and available in publicdatabases such as GenBank or other private sequence databases. Sequenceidentity (at either the amino acid or nucleotide level) within definedregions of the molecule or across the full-length sequence can bedetermined using methods known in the art and as described herein.

Nucleic acid having protein coding sequence may be obtained by screeningselected cDNA or genomic libraries using the deduced amino acid sequencedisclosed herein for the first time, and, if necessary, usingconventional primer extension procedures as described in Sambrook etal., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

Host cells are transfected or transformed with expression or cloningvectors described herein for PRO production and cultured in conventionalnutrient media modified as appropriate for inducing promoters, selectingtransformants, or amplifying the genes encoding the desired sequences.The culture conditions, such as media, temperature, pH and the like, canbe selected by the skilled artisan without undue experimentation. Ingeneral, principles, protocols, and practical techniques for maximizingthe productivity of cell cultures can be found in Mammalian CellBiotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991)and Sambrook et al., supra.

Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456-457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130:946(1977) and Hsiao et al.,Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, other methods forintroducing DNA into cells, such as by nuclear microinjection,electroporation, bacterial protoplast fusion with intact cells, orpolycations, e.g., polybrene, polyornithine, may also be used. Forvarious techniques for transforming mammalian cells, see Keown et al.,Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature,336:348-352 (1988).

Suitable host cells for cloning or expressing the DNA in the vectorsherein include prokaryote, yeast, or higher eukaryote cells. Suitableprokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium,Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacillisuch as B. subtilis and B. licheniformis (e.g., B. licheniformis 41Pdisclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P.aeruginosa, and Streptomyces. These examples are illustrative ratherthan limiting. Strain W3110 is one particularly preferred host or parenthost because it is a common host strain for recombinant DNA productfermentations. Preferably, the host cell secretes minimal amounts ofproteolytic enzymes. For example, strain W3110 may be modified to effecta genetic mutation in the genes encoding proteins endogenous to thehost, with examples of such hosts including E. coli W3110 strain 1A2,which has the complete genotype tonA; E. coli W3110 strain 9E4, whichhas the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC55,244), which has the complete genotype tonAptr3phoA E15 (argF-lac)169degP ompT kan^(r) ; E. coli W3110 strain 37D6, which has the completegenotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan^(r) ,E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycinresistant degP deletion mutation; and an E. coli strain having mutantperiplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued Aug. 7,1990. Alternatively, in vitro methods of cloning, e.g., PCR or othernucleic acid polymerase reactions, are suitable.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts for PRO-encodingvectors. Saccharomyces cerevisiae is a commonly used lower eukaryotichost microorganism. Others include Schizosaccharomyces pombe (Beach andNurse, Nature, 290:140 [1981]; EP 139,383 published May 2, 1985);Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al.,Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C,CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 [1983]), K.fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van denBerg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K.marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070;Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida;Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc.Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such asSchwanniomyces occidentalis (EP 394,538 published Oct. 31, 1990); andfilamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium(WO 91/00357 published Jan. 10, 1991), and Aspergillus hosts such as A.nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289[1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc.Natl. Acad. Sci. USA, 81:1470-1474 [1984]) and A. niger (Kelly andHynes, EMBO J., 4:475479 [1985]). Methylotropic yeasts are suitableherein and include, but are not limited to, yeast capable of growth onmethanol selected from the genera consisting of Hansenula, Candida,Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list ofspecific species that are exemplary of this class of yeasts may be foundin C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).

Suitable host cells for the expression of glycosylated PRO are derivedfrom multicellular organisms. Examples of invertebrate cells includeinsect cells such as Drosophila S2 and Spodoptera Sf9, as well as plantcells. Examples of useful mammalian host cell lines include Chinesehamster ovary (CHO) and COS cells. More specific examples include monkeykidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); humanembryonic kidney line (293 or 293 cells subcloned for growth insuspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinesehamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad.Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol.Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); humanliver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCCCCL51). The selection of the appropriate host cell is deemed to bewithin the skill in the art.

3. Selection and Use of a Replicable Vector

The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of the DNA)or for expression. Various vectors are publicly available. The vectormay, for example, be in the form of a plasmid, cosmid, viral particle,or phage. The appropriate nucleic acid sequence may be inserted into thevector by a variety of procedures. In general, DNA is inserted into anappropriate restriction endonuclease site(s) using techniques known inthe art. Vector components generally include, but are not limited to,one or more of a signal sequence, an origin of replication, one or moremarker genes, an enhancer element, a promoter, and a transcriptiontermination sequence. Construction of suitable vectors containing one ormore of these components employs standard ligation techniques which areknown to the skilled artisan.

The PRO may be produced recombinantly not only directly, but also as afusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe PRO-encoding DNA that is inserted into the vector. The signalsequence may be a prokaryotic signal sequence selected, for example,from the group of the alkaline phosphatase, penicillinase, 1pp, orheat-stable enterotoxin II leaders. For yeast secretion the signalsequence may be, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces α-factor leaders, the latterdescribed in U.S. Pat. No. 5,010,182), or acid phosphatase leader, theC. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), orthe signal described in WO 90/13646 published Nov. 15, 1990. Inmammalian cell expression, mammalian signal sequences may be used todirect secretion of the protein, such as signal sequences from secretedpolypeptides of the same or related species, as well as viral secretoryleaders.

Both expression and cloning vectors contain a nucleic acid sequence thatenables the vector to replicate in one or more selected host cells. Suchsequences are well known for a variety of bacteria, yeast, and viruses.The origin of replication from the plasmid pBR322 is suitable for mostGram-negative bacteria, the 2μ plasmid origin is suitable for yeast, andvarious viral origins (SV40, polyoma, adenovirus, VSV or BPV) are usefulfor cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene,also termed a selectable marker. Typical selection genes encode proteinsthat (a) confer resistance to antibiotics or other toxins, e.g.,ampicillin, neomycin, methotrexate, or tetracycline, (b) complementauxotrophic deficiencies, or (c) supply critical nutrients not availablefrom complex media, e.g., the gene encoding D-alanine racemase forBacilli.

An example of suitable selectable markers for mammalian cells are thosethat enable the identification of cells competent to take up thePRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHO cellline deficient in DHFR activity, prepared and propagated as described byUrlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitableselection gene for use in yeast is the trp1 gene present in the yeastplasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al.,Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1gene provides a selection marker for a mutant strain of yeast lackingthe ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1[Jones, Genetics, 85:12 (1977)].

Expression and cloning vectors usually contain a promoter operablylinked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential host cells arewell known. Promoters suitable for use with prokaryotic hosts includethe β-lactamase and lactose promoter systems [Chang et al., Nature,275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkalinephosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic AcidsRes., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tacpromoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)].Promoters for use in bacterial systems also will contain aShine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growth conditions,are the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

PRO transcription from vectors in mammalian host cells is controlled,for example, by promoters obtained from the genomes of viruses such aspolyoma virus, fowlpox virus (UK 2,211,504 published Jul. 5, 1989),adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcomavirus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus40 (SV40), from heterologous mammalian promoters, e.g., the actinpromoter or an immunoglobulin promoter, and from heat-shock promoters,provided such promoters are compatible with the host cell systems.

Transcription of a DNA encoding the PRO by higher eukaryotes may beincreased by inserting an enhancer sequence into the vector. Enhancersare cis-acting elements of DNA, usually about from 10 to 300 bp, thatact on a promoter to increase its transcription. Many enhancer sequencesare now known from mammalian genes (globin, elastase, albumin,α-fetoprotein, and insulin). Typically, however, one will use anenhancer from a eukaryotic cell virus. Examples include the SV40enhancer on the late side of the replication origin (bp 100-270), thecytomegalovirus early promoter enhancer, the polyoma enhancer on thelate side of the replication origin, and adenovirus enhancers. Theenhancer may be spliced into the vector at a position 5′ or 3′ to thePRO coding sequence, but is preferably located at a site 5′ from thepromoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insect,plant, animal, human, or nucleated cells from other multicellularorganisms) will also contain sequences necessary for the termination oftranscription and for stabilizing the mRNA. Such sequences are commonlyavailable from the 5′ and, occasionally 3′, untranslated regions ofeukaryotic or viral DNAs or cDNAs. These regions contain nucleotidesegments transcribed as polyadenylated fragments in the untranslatedportion of the mRNA encoding PRO.

Still other methods, vectors, and host cells suitable for adaptation tothe synthesis of PRO in recombinant vertebrate cell culture aredescribed in Gething et al., Nature 293:620-625 (1981); Mantei et al.,Nature, 281:4046 (1979); EP 117,060; and EP 117,058.

4. Detecting Gene Amplification/Expression

Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or insitu hybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

Gene expression, alternatively, may be measured by immunologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequencePRO polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to PRO DNAand encoding a specific antibody epitope.

5. Purification of Polypeptide

Forms of PRO may be recovered from culture medium or from host celllysates. If membrane-bound, it can be released from the membrane using asuitable detergent solution (e.g. Triton-X 100) or by enzymaticcleavage. Cells employed in expression of PRO can be disrupted byvarious physical or chemical means, such as freeze-thaw cycling,sonication, mechanical disruption, or cell lysing agents.

It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchange column;ethanol precipitation; reverse phase HPLC; chromatography on silica oron a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE;ammonium sulfate precipitation; gel filtration using, for example,Sephadex G-75; protein A Sepharose columns to remove contaminants suchas IgG; and metal chelating columns to bind epitope-tagged forms of thePRO. Various methods of protein purification may be employed and suchmethods are known in the art and described for example in Deutscher,Methods in Enzymology, 182 (1990); Scopes, Protein Purification:Principles and Practice, Springer-Verlag, New York (1982). Thepurification step(s) selected will depend, for example, on the nature ofthe production process used and the particular PRO produced.

E. Uses for PRO

Nucleotide sequences (or their complement) encoding PRO have variousapplications in the art of molecular biology, including uses ashybridization probes, in chromosome and gene mapping and in thegeneration of anti-sense RNA and DNA. PRO nucleic acid will also beuseful for the preparation of PRO polypeptides by the recombinanttechniques described herein.

The full-length native sequence PRO gene, or portions thereof, may beused as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO from otherspecies) which have a desired sequence identity to the native PROsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence PRO. By way of example, ascreening method will comprise isolating the coding region of the PROgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or 35S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the PRO gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below.

Any EST sequences disclosed in the present application may similarly beemployed as probes, using the methods disclosed herein.

Other useful fragments of the PRO nucleic acids include antisense orsense oligonucleotides comprising a singe-stranded nucleic acid sequence(either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRODNA (antisense) sequences. Antisense or sense oligonucleotides,according to the present invention, comprise a fragment of the codingregion of PRO DNA. Such a fragment generally comprises at least about 14nucleotides, preferably from about 14 to 30 nucleotides. The ability toderive an antisense or a sense oligonucleotide, based upon a cDNAsequence encoding a given protein is described in, for example, Steinand Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al.(BioTechniques 6:958, 1988).

Binding of antisense or sense oligonucleotides to target nucleic acidsequences results in the formation of duplexes that block transcriptionor translation of the target sequence by one of several means, includingenhanced degradation of the duplexes, premature termination oftranscription or translation, or by other means. The antisenseoligonucleotides thus may be used to block expression of PRO proteins.Antisense or sense oligonucleotides further comprise oligonucleotideshaving modified sugar-phosphodiester backbones (or other sugar linkages,such as those described in WO 91/06629) and wherein such sugar linkagesare resistant to endogenous nucleases. Such oligonucleotides withresistant sugar linkages are stable in vivo (i.e., capable of resistingenzymatic degradation) but retain sequence specificity to be able tobind to target nucleotide sequences.

Other examples of sense or antisense oligonucleotides include thoseoligonucleotides which are covalently linked to organic moieties, suchas those described in WO 90/10048, and other moieties that increasesaffinity of the oligonucleotide for a target nucleic acid sequence, suchas poly-(L-lysine). Further still, intercalating agents, such asellipticine, and alkylating agents or metal complexes may be attached tosense or antisense oligonucleotides to modify binding specificities ofthe antisense or sense oligonucleotide for the target nucleotidesequence.

Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, CaPO₄-mediated DNA transfection,electroporation, or by using gene transfer vectors such as Epstein-Barrvirus. In a preferred procedure, an antisense or sense oligonucleotideis inserted into a suitable retroviral vector. A cell containing thetarget nucleic acid sequence is contacted with the recombinantretroviral vector, either in vivo or ex vivo. Suitable retroviralvectors include, but are not limited to, those derived from the murineretrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the doublecopy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

Sense or antisense oligonucleotides also may be introduced into a cellcontaining the target nucleotide sequence by formation of a conjugatewith a ligand binding molecule, as described in WO 91/04753. Suitableligand binding molecules include, but are not limited to, cell surfacereceptors, growth factors, other cytokines, or other ligands that bindto cell surface receptors. Preferably, conjugation of the ligand bindingmolecule does not substantially interfere with the ability of the ligandbinding molecule to bind to its corresponding molecule or receptor, orblock entry of the sense or antisense oligonucleotide or its conjugatedversion into the cell.

Alternatively, a sense or an antisense oligonucleotide may be introducedinto a cell containing the target nucleic acid sequence by formation ofan oligonucleotide-lipid complex, as described in WO 90/10448. The senseor antisense oligonucleotide-lipid complex is preferably dissociatedwithin the cell by an endogenous lipase.

Antisense RNA or DNA molecules are generally at least about 5 bases inlength, about 10 bases in length, about 15 bases in length, about 20bases in length, about 25 bases in length, about 30 bases in length,about 35 bases in length, about 40 bases in length, about 45 bases inlength, about 50 bases in length, about 55 bases in length, about 60bases in length, about 65 bases in length, about 70 bases in length,about 75 bases in length, about 80 bases in length, about 85 bases inlength, about 90 bases in length, about 95 bases in length, about 100bases in length, or more.

The probes may also be employed in PCR techniques to generate a pool ofsequences for identification of closely related PRO coding sequences.

Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PRO and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor PRO can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native PRO or a receptor for PRO. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein—protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

Nucleic acids which encode PRO or its modified forms can also be used togenerate either transgenic animals or “knock out” animals which, inturn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic animal develops. In oneembodiment, cDNA encoding PRO can be used to clone genomic DNA encodingPRO in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding PRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for PRO transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding PRO introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding PRO. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

Alternatively, non-human homologues of PRO can be used to construct aPRO “knock out” animal which has a defective or altered gene encodingPRO as a result of homologous recombination between the endogenous geneencoding PRO and altered genomic DNA encoding PRO introduced into anembryonic stem cell of the animal. For example, cDNA encoding PRO can beused to clone genomic DNA encoding PRO in accordance with establishedtechniques. A portion of the genomic DNA encoding PRO can be deleted orreplaced with another gene, such as a gene encoding a selectable markerwhich can be used to monitor integration. Typically, several kilobasesof unaltered flanking DNA (both at the 5′ and 3′ ends) are included inthe vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for adescription of homologous recombination vectors]. The vector isintroduced into an embryonic stem cell line (e.g., by electroporation)and cells in which the introduced DNA has homologously recombined withthe endogenous DNA are selected [see e.g., Li et al., Cell, 69:915(1992)]. The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse or rat) to form aggregation chimeras [see e.g.,Bradley, in Teratocarcinomas and Embryonic Stem Cells:A PracticalApproach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. Achimeric embryo can then be implanted into a suitable pseudopregnantfemale foster animal and the embryo brought to term to create a “knockout” animal. Progeny harboring the homologously recombined DNA in theirgerm cells can be identified by standard techniques and used to breedanimals in which all cells of the animal contain the homologouslyrecombined DNA. Knockout animals can be characterized for instance, fortheir ability to defend against certain pathological conditions and fortheir development of pathological conditions due to absence of the PROpolypeptide.

Nucleic acid encoding the PRO polypeptides may also be used in genetherapy. In gene therapy applications, genes are introduced into cellsin order to achieve in vivo synthesis of a therapeutically effectivegenetic product, for example for replacement of a defective gene. “Genetherapy” includes both conventional gene therapy where a lasting effectis achieved by a single treatment, and the administration of genetherapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83:41434146 [1986]). The oligonucleotides can bemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

There are a variety of techniques available for introducing nucleicacids into viable cells. The techniques vary depending upon whether thenucleic acid is transferred into cultured cells in vitro, or in vivo inthe cells of the intended host. Techniques suitable for the transfer ofnucleic acid into mammalian cells in vitro include the use of liposomes,electroporation, microinjection, cell fusion, DEAE-dextran, the calciumphosphate precipitation method, etc. The currently preferred in vivogene transfer techniques include transfection with viral (typicallyretroviral) vectors and viral coat protein-liposome mediatedtransfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]).In some situations it is desirable to provide the nucleic acid sourcewith an agent that targets the target cells, such as an antibodyspecific for a cell surface membrane protein or the target cell, aligand for a receptor on the target cell, etc. Where liposomes areemployed, proteins which bind to a cell surface membrane proteinassociated with endocytosis may be used for targeting and/or tofacilitate uptake, e.g. capsid proteins or fragments thereof tropic fora particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

The PRO polypeptides described herein may also be employed as molecularweight markers for protein electrophoresis purposes and the isolatednucleic acid sequences may be used for recombinantly expressing thosemarkers.

The nucleic acid molecules encoding the PRO polypeptides or fragmentsthereof described herein are useful for chromosome identification. Inthis regard, there exists an ongoing need to identify new chromosomemarkers, since relatively few chromosome marking reagents, based uponactual sequence data are presently available. Each PRO nucleic acidmolecule of the present invention can be used as a chromosome marker.

The PRO polypeptides and nucleic acid molecules of the present inventionmay also be used for tissue typing, wherein the PRO polypeptides of thepresent invention may be differentially expressed in one tissue ascompared to another. PRO nucleic acid molecules will find use forgenerating probes for PCR, Northern analysis, Southern analysis andWestern analysis.

The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present invention can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the PRO product hereof is combined in admixturewith a pharmaceutically acceptable carrier vehicle. Therapeuticformulations are prepared for storage by mixing the active ingredienthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptides; proteins,such as serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides and othercarbohydrates including glucose, mannose, or dextrins; chelating agentssuch as EDTA; sugar alcohols such as mannitol or sorbitol; salt-formingcounterions such as sodium; and/or nonionic surfactants such as TWEEN™,PLURONICS™0 or PEG.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes, prior to or following lyophilization and reconstitution.

Therapeutic compositions herein generally are placed into a containerhaving a sterile access port, for example, an intravenous solution bagor vial having a stopper pierceable by a hypodermic injection needle.

The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal, intracerebral,intramuscular, intraocular, intraarterial or intralesional routes,topical administration, or by sustained release systems.

Dosages and desired drug concentrations of pharmaceutical compositionsof the present invention may vary depending on the particular useenvisioned. The determination of the appropriate dosage or route ofadministration is well within the skill of an ordinary physician. Animalexperiments provide reliable guidance for the determination of effectivedoses for human therapy. Interspecies scaling of effective doses can beperformed following the principles laid down by Mordenti, J. andChappell, W. “The use of interspecies scaling in toxicokinetics” InToxicokinetics and New Drug Development, Yacobi et al., Eds., PergamonPress, New York 1989, pp. 42-96.

When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day,preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the routeof administration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212. It is anticipated that differentformulations will be effective for different treatment compounds anddifferent disorders, that administration targeting one organ or tissue,for example, may necessitate delivery in a manner different from that toanother organ or tissue.

Where sustained-release administration of a PRO polypeptide is desiredin a formulation with release characteristics suitable for the treatmentof any disease or disorder requiring administration of the PROpolypeptide, microencapsulation of the PRO polypeptide is contemplated.Microencapsulation of recombinant proteins for sustained release hasbeen successfully performed with human growth hormone (rhGH),interferon-(rhIFN- ), interleukin-2, and MN rgp120. Johnson et al., Nat.Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Horaet al., Bio/Technology, 8:755-758 (1990); Cleland, “Design andProduction of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems,” in Vaccine Design: The Subunit andAdjuvant Approach, Powell and Newman, eds, (Plenum Press: New York,1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

The sustained-release formulations of these proteins were developedusing poly-lactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can be clearedquickly within the human body. Moreover, the degradability of thispolymer can be adjusted from months to years depending on its molecularweight and composition. Lewis, “Controlled release of bioactive agentsfrom lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.),Biodegradable Polymers as Drum Delivery Systems (Marcel Dekker: NewYork, 1990), pp. 1-41.

This invention encompasses methods of screening compounds to identifythose that mimic the PRO polypeptide (agonists) or prevent the effect ofthe PRO polypeptide (antagonists). Screening assays for antagonist drugcandidates are designed to identify compounds that bind or complex withthe PRO polypeptides encoded by the genes identified herein, orotherwise interfere with the interaction of the encoded polypeptideswith other cellular proteins. Such screening assays will include assaysamenable to high-throughput screening of chemical libraries, making themparticularly suitable for identifying small molecule drug candidates.

The assays can be performed in a variety of formats, includingprotein—protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

All assays for antagonists are common in that they call for contactingthe drug candidate with a PRO polypeptide encoded by a nucleic acididentified herein under conditions and for a time sufficient to allowthese two components to interact.

In binding assays, the interaction is binding and the complex formed canbe isolated or detected in the reaction mixture. In a particularembodiment, the PRO polypeptide encoded by the gene identified herein orthe drug candidate is immobilized on a solid phase, e.g., on amicrotiter plate, by covalent or non-covalent attachments. Non-covalentattachment generally is accomplished by coating the solid surface with asolution of the PRO polypeptide and drying. Alternatively, animmobilized antibody, e.g., a monoclonal antibody, specific for the PROpolypeptide to be immobilized can be used to anchor it to a solidsurface. The assay is performed by adding the non-immobilized component,which may be labeled by a detectable label, to the immobilizedcomponent, e.g., the coated surface containing the anchored component.When the reaction is complete, the non-reacted components are removed,e.g., by washing, and complexes anchored on the solid surface aredetected. When the originally non-immobilized component carries adetectable label, the detection of label immobilized on the surfaceindicates that complexing occurred. Where the originally non-immobilizedcomponent does not carry a label, complexing can be detected, forexample, by using a labeled antibody specifically binding theimmobilized complex.

If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein—protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein—protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340:245-246 (1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA,89:5789-5793 (1991). Many transcriptional activators, such as yeastGAL4, consist of two physically discrete modular domains, one acting asthe DNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein—protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™)for identifying protein—protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

Compounds that interfere with the interaction of a gene encoding a PROpolypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

To assay for antagonists, the PRO polypeptide may be added to a cellalong with the compound to be screened for a particular activity and theability of the compound to inhibit the activity of interest in thepresence of the PRO polypeptide indicates that the compound is anantagonist to the PRO polypeptide. Alternatively, antagonists may bedetected by combining the PRO polypeptide and a potential antagonistwith membrane-bound PRO polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The PROpolypeptide can be labeled, such as by radioactivity, such that thenumber of PRO polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the PRO polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the PROpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled PRO polypeptide. The PRO polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

As an alternative approach for receptor identification, labeled PROpolypeptide can be photoaffinity-linked with cell membrane or extractpreparations that express the receptor molecule. Cross-linked materialis resolved by PAGE and exposed to X-ray film. The labeled complexcontaining the receptor can be excised, resolved into peptide fragments,and subjected to protein micro-sequencing. The amino acid sequenceobtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled PROpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with PROpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the PROpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the PRO polypeptide.

Another potential PRO polypeptide antagonist is an antisense RNA or DNAconstruct prepared using antisense technology, where, e.g., an antisenseRNA or DNA molecule acts to block directly the translation of mRNA byhybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to control gene expression throughtriple-helix formation or antisense DNA or RNA, both of which methodsare based on binding of a polynucleotide to DNA or RNA. For example, the5′ coding portion of the polynucleotide sequence, which encodes themature PRO polypeptides herein, is used to design an antisense RNAoligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription (triple helix - see Lee et al., Nucl. AcidsRes., 6:3073 (1979); Cooney et al., Science, 241:456 (1988); Dervan etal., Science, 251:1360 (1991)), thereby preventing transcription and theproduction of the PRO polypeptide. The antisense RNA oligonucleotidehybridizes to the mRNA in vivo and blocks translation of the mRNAmolecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560(1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression(CRC Press: Boca Raton, Fla., 1988). The oligonucleotides describedabove can also be delivered to cells such that the antisense RNA or DNAmay be expressed in vivo to inhibit production of the PRO polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

Potential antagonists include small molecules that bind to the activesite, the receptor binding site, or growth factor or other relevantbinding site of the PRO polypeptide, thereby blocking the normalbiological activity of the PRO polypeptide. Examples of small moleculesinclude, but are not limited to, small peptides or peptide-likemolecules, preferably soluble peptides, and synthetic non-peptidylorganic or inorganic compounds.

Ribozymes are enzymatic RNA molecules capable of catalyzing the specificcleavage of RNA. Ribozymes act by sequence-specific hybridization to thecomplementary target RNA, followed by endonucleolytic cleavage. Specificribozyme cleavage sites within a potential RNA target can be identifiedby known techniques. For further details see, e.g., Rossi, CurrentBiology, 4:469471 (1994), and PCT publication No. WO 97/33551 (publishedSep. 18, 1997).

Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

With regard to the PRO211 and PRO217 polypeptide, therapeuticindications include disorders associated with the preservation andmaintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellisonsyndrome, gastrointestinal ulceration and congenital microvillusatrophy), skin diseases associated with abnormal keratinocytedifferentiation (e.g., psoriasis, epithelial cancers such as lungsquamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.

Since the PRO232 polypeptide and nucleic acid encoding it possesssequence homology to a cell surface stem cell antigen and its encodingnucleic acid, probes based upon the PRO232 nucleotide sequence may beemployed to identify other novel stem cell surface antigen proteins.Soluble forms of the PRO232 polypeptide may be employed as antagonistsof membrane bound PRO232 activity both in vitro and in vivo. PRO232polypeptides may be employed in screening assays designed to identifyagonists or antagonists of the native PRO232 polypeptide, wherein suchassays may take the form of any conventional cell-type or biochemicalbinding assay. Moreover, the PRO232 polypeptide may serve as a molecularmarker for the tissues in which the polypeptide is specificallyexpressed.

With regard to the PRO187 polypeptides disclosed herein, FGF-8 has beenimplicated in cellular differentiation and embryogenesis, including thepatterning which appears during limb formation. FGF-8 and the PRO187molecules of the invention therefore are likely to have potent effectson cell growth and development. Diseases which relate to cellular growthand differentiation are therefore suitable targets for therapeuticsbased on functionality similar to FGF-8. For example, diseases relatedto growth or survival of nerve cells including Parkinson's disease,Alzheimer's disease, ALS, neuropathies. Additionally, disease related touncontrolled cell growth, e.g., cancer, would also be expectedtherapeutic targets.

With regard to the PRO265 polypeptides disclosed herein, other methodsfor use with PRO265 are described in U.S. Pat. 5,654,270 to Ruoslahti etal. In particular, PRO265 can be used in comparison with thefibromodulin disclosed therein to compare its effects on reducing dermalscarring and other properties of the fibromodulin described thereinincluding where it is located and with what it binds and does not.

The PRO219 polypeptides of the present invention which play a regulatoryrole in the blood coagulation cascade may be employed in vivo fortherapeutic purposes as well as for in vitro purposes. Those of ordinaryskill in the art will well know how to employ PRO219 polypeptides forsuch uses.

The PRO246 polypeptides of the present invention which serve as cellsurface receptors for one or more viruses will find other uses. Forexample, extracellular domains derived from these PRO246 polypeptidesmay be employed therapeutically in vivo for lessening the effects ofviral infection. Those PRO246 polypeptides which serves as tumorspecific antigens may be exploited as therapeutic targets for anti-tumordrugs, and the like. Those of ordinary skill in the art will well knowhow to employ PRO246 polypeptides for such uses.

Assays in which connective growth factor and other growth factors areusually used should be performed with PRO261. An assay to determinewhether TGF beta induces PRO261, indicating a role in cancer isperformed as known in the art. Wound repair and tissue growth assays arealso performed with PRO261. The results are applied accordingly.

PRO228 polypeptides should be used in assays in which EMR1, CD97 andlatrophilin would be used in to determine their relative activities. Theresults can be applied accordingly. For example, a competitive bindingassay with PRO228 and CD97 can be performed with the ligand for CD97,CD55.

Native PRO533 is a 216 amino acid polypeptide of which residues 1-22 arethe signal sequence. Residues 3 to 216 have a Blast score of 509,corresponding to 53% homology to fibroblast growth factor. At thenucleotide level, DNA47412, the EST from which PCR oligos were generatedto isolate the full length DNA49435-1219, has been observed to map to11p15. Sequence homology to the 11p15 locus would indicate that PRO533may have utility in the treatment of Usher Syndrome or Atrophia areata.

As mentioned previously, fibroblast growth factors can act upon cells inboth a mitogenic and non-mitogenic manner. These factors are mitogenicfor a wide variety of normal diploid mesoderm-derived and neuralcrest-derived cells, inducing granulosa cells, adrenal cortical cells,chrondrocytes, myoblasts, corneal and vascular endothelial cells (bovineor human), vascular smooth muscle cells, lens, retina and prostaticepithelial cells, oligodendrocytes, astrocytes, chrondocytes, myoblastsand osteoblasts.

Non-mitogenic actions of fibroblast growth factors include promotion ofcell migration into a wound area (chemotaxis), initiation of new bloodvessel formulation (angiogenesis), modulation of nerve regeneration andsurvival (neurotrophism), modulation of endocrine functions, andstimulation or suppression of specific cellular protein expression,extracellular matrix production and cell survival. Baird, A. & Bohlen,P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These propertiesprovide a basis for using fibroblast growth factors in therapeuticapproaches to accelerate wound healing, nerve repair, collateral bloodvessel formation, and the like. For example, fibroblast growth factors,have been suggested to minimize myocardium damage in heart disease andsurgery (U.S. Pat. No. 4,378,437).

Since the PRO245 polypeptide and nucleic acid encoding it possesssequence homology to a transmembrane protein tyrosine kinase protein andits encoding nucleic acid, probes based upon the PRO245 nucleotidesequence may be employed to identify other novel transmembrane tyrosinekinase proteins. Soluble forms of the PRO245 polypeptide may be employedas antagonists of membrane bound PRO245 activity both in vitro and invivo. PRO245 polypeptides may be employed in screening assays designedto identify agonists or antagonists of the native PRO245 polypeptide,wherein such assays may take the form of any conventional cell-type orbiochemical binding assay. Moreover, the PRO245 polypeptide may serve asa molecular marker for the tissues in which the polypeptide isspecifically expressed.

PRO220, PRO221 and PRO227 all have leucine rich repeats. Additionally,PRO220 and PRO221 have homology to SLIT and leucine rich repeat protein.Therefore, these proteins are useful in assays described in theliterature, supra, wherein the SLIT and leucine rich repeat protein areused. Regarding the SLIT protein, PRO227 can be used in an assay todetermine the affect of PRO227 on neurodegenerative disease.Additionally, PRO227 has homology to human glycoprotein V. In the caseof PRO227, this polypeptide is used in an assay to determine its affecton bleeding, clotting, tissue repair and scarring.

The PRO266 polypeptide can be used in assays to determine if it has arole in neurodegenerative diseases or their reversal.

PRO269 polypeptides and portions thereof which effect the activity ofthrombin may also be useful for in vivo therapeutic purposes, as well asfor various in vitro applications. In addition, PRO269 polypeptides andportions thereof may have therapeutic use as an antithrombotic agentwith reduced risk for hemorrhage as compared with heparin. Peptideshaving homology to thrombomodulin are particularly desirable.

PRO287 polypeptides and portions thereof which effect the activity ofbone morphogenic protein “BMP1”/procollagen C-proteinase (PCP) may alsobe useful for in vivo therapeutic purposes, as well as for various invitro applications. In addition, PRO287 polypeptides and portionsthereof may have therapeutic applications in wound healing and tissuerepair. Peptides having homology to procollagen C-proteinase enhancerprotein and its precursor may also be used to induce bone and/orcartilage formation and are therefore of particular interest to thescientific and medical communities.

Therapeutic indications for PRO214 polypeptides include disordersassociated with the preservation and maintenance of gastrointestinalmucosa and the repair of acute and chronic mucosal lesions (e.g.,enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationand congenital microvillus atrophy), skin diseases associated withabnormal keratinocyte differentiation (e.g., psoriasis, epithelialcancers such as lung squamous cell carcinoma, epidermoid carcinoma ofthe vulva and gliomas.

Studies on the generation and analysis of mice deficient in members ofthe TGF—superfamily are reported in Matzuk, Trends in Endocrinol, andMetabol., 6:120-127 (1995).

The PRO317 polypeptide, as well as PRO317-specific antibodies,inhibitors, agonists, receptors, or their analogs, herein are useful intreating PRO317-associated disorders. Hence, for example, they may beemployed in modulating endometrial bleeding angiogenesis, and may alsohave an effect on kidney tissue. Endometrial bleeding can occur ingynecological diseases such as endometrial cancer as abnormal bleeding.Thus, the compositions herein may find use in diagnosing and treatingabnormal bleeding conditions in the endometrium, as by reducing oreliminating the need for a hysterectomy. The molecules herein may alsofind use in angiogenesis applications such as anti-tumor indications forwhich the antibody against vascular endothelial growth factor is used,or, conversely, ischemic indications for which vascular endothelialgrowth factor is employed.

Bioactive compositions comprising PRO317 or agonists or antagoniststhereof may be administered in a suitable therapeutic dose determined byany of several methodologies including clinical studies on mammalianspecies to determine maximal tolerable dose and on normal human subjectsto determine safe dose. Additionally, the bioactive agent may becomplexed with a variety of well established compounds or compositionswhich enhance stability or pharmacological properties such as half-life.It is contemplated that the therapeutic, bioactive composition may bedelivered by intravenous infusion into the bloodstream or any othereffective means which could be used for treating problems of the kidney,uterus, endometrium, blood vessels, or related tissue, e.g., in theheart or genital tract.

Dosages and administration of PRO317, PRO317 agonist, or PRO317antagonist in a pharmaceutical composition may be determined by one ofordinary skill in the art of clinical pharmacology or pharmacokinetics.See, for example, Mordenti and Rescigno, Pharmaceutical Research,9:17-25 (1992); Morenti et al., Pharmaceutical Research, 8:1351-1359(1991); and Mordenti and Chappell, “The use of interspecies scaling intoxicokinetics” in Toxicokinetics and New Drug Development, Yacobi etal. (eds) (Pergamon Press: NY, 1989), pp. 42-96. An effective amount ofPRO317, PRO317 agonist, or PRO317 antagonist to be employedtherapeutically will depend, for example, upon the therapeuticobjectives, the route of administration, and the condition of themammal. Accordingly, it will be necessary for the therapist to titer thedosage and modify the route of administration as required to obtain theoptimal therapeutic effect. A typical daily dosage might range fromabout 10 ng/kg to up to 100 mg/kg of the mammal's body weight or moreper day, preferably about 1 μg/kg/day to 10 mg/kg/day. Typically, theclinician will administer PRO317, PRO317 agonist, or PRO317 antagonist,until a dosage is reached that achieves the desired effect for treatmentof the above mentioned disorders.

PRO317 or an PRO317 agonist or PRO317 antagonist may be administeredalone or in combination with another to achieve the desiredpharmacological effect. PRO317 itself, or agonists or antagonists ofPRO317 can provide different effects when administered therapeutically.Such compounds for treatment will be formulated in a nontoxic, inert,pharmaceutically acceptable aqueous carrier medium preferably at a pH ofabout 5 to 8, more preferably 6 to 8, although the pH may vary accordingto the characteristics of the PRO317, agonist, or antagonist beingformulated and the condition to be treated. Characteristics of thetreatment compounds include solubility of the molecule, half-life, andantigenicity/immunogenicity; these and other characteristics may aid indefining an effective carrier.

PRO317 or PRO317 agonists or PRO317 antagonists may be delivered byknown routes of administration including but not limited to topicalcreams and gels; transmucosal spray and aerosol, transdermal patch andbandage; injectable, intravenous, and lavage formulations; and orallyadministered liquids and pills, particularly formulated to resiststomach acid and enzymes. The particular formulation, exact dosage, androute of administration will be determined by the attending physicianand will vary according to each specific situation.

Such determinations of administration are made by considering multiplevariables such as the condition to be treated, the type of mammal to betreated, the compound to be administered, and the pharmacokineticprofile of the particular treatment compound. Additional factors whichmay be taken into account include disease state (e.g. severity) of thepatient, age, weight, gender, diet, time of administration, drugcombination, reaction sensitivities, and tolerance/response to therapy.Long-acting treatment compound formulations (such as liposomallyencapsulated PRO317 or PEGylated PRO317 or PRO317 polymericmicrospheres, such as polylactic acid-based microspheres) might beadministered every 3 to 4 days, every week, or once every two weeksdepending on half-life and clearance rate of the particular treatmentcompound.

Normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg ofmammal body weight or more per day, preferably about 1 μg/kg/day to 10mg/kg/day, depending upon the route of administration. Guidance as toparticular dosages and methods of delivery is provided in theliterature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or5,225,212. It is anticipated that different formulations will beeffective for different treatment compounds and different disorders,that administration targeting the uterus, for example, may necessitatedelivery in a manner different from that to another organ or tissue,such as cardiac tissue.

Where sustained-release administration of PRO317 is desired in aformulation with release characteristics suitable for the treatment ofany disease or disorder requiring administration of PRO317,microencapsulation of PRO317 is contemplated. Microencapsulation ofrecombinant proteins for sustained release has been successfullyperformed with human growth hormone (rhGH), interferon- (rhIFN-),interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2:795-799(1996); Yasuda, Biomed. Ther., 27: 1221-1223 (1993); Hora et al.,Bio/Technology 8:755-758 (1990); Cleland, “Design and Production ofSingle Immunization Vaccines Using Polylactide Polyglycolide MicrosphereSystems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powelland Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO97/03692, WO 96140072, WO 96/07399; and U.S. Pat. No. 5,654,010.

It is contemplated that conditions or diseases of the uterus,endometrial tissue, or other genital tissues or cardiac tissues mayprecipitate damage that is treatable with PRO317 or PRO317 agonist wherePRO317 expression is reduced in the diseased state; or with antibodiesto PRO317 or other PRO317 antagonists where the expression of PRO317 isincreased in the diseased state. These conditions or diseases may bespecifically diagnosed by the probing tests discussed above forphysiologic and pathologic problems which affect the function of theorgan.

The PRO317, PRO317 agonist, or PRO317 antagonist may be administered toa mammal with another biologically active agent, either separately or inthe same formulation to treat a common indication for which they areappropriate. For example, it is contemplated that PRO317 can beadministered together with EBAF-1 for those indications on which theydemonstrate the same qualitative biological effects. Alternatively,where they have opposite effects, EBAF-1 may be administered togetherwith an antagonist to PRO317, such as an anti-PRO317 antibody. Further,PRO317 may be administered together with VEGF for coronary ischemiawhere such indication is warranted, or with an anti-VEGF for cancer aswarranted, or, conversely, an antagonist to PRO317 may be administeredwith VEGF for coronary ischemia or with anti-VEGF to treat cancer aswarranted. These administrations would be in effective amounts fortreating such disorders.

Native PRO301 (SEQ ID NO:119) has a Blast score of 246 and 30% homologyat residues 24 to 282 of FIG. 44 with A33_HUMAN, an A33 antigenprecursor. A33 antigen precursor, as explained in the Background is atumor-specific antigen, and as such, is a recognized marker andtherapeutic target for the diagnosis and treatment of colon cancer. Theexpression of tumor-specific antigens is often associated with theprogression of neoplastic tissue disorders. Native PRO301 (SEQ IDNO:119) and A33_HUMAN also show a Blast score of 245 and 30% homology atresidues 21 to 282 of FIG. 44 with A33_HUMAN, the variation dependentupon how spaces are inserted into the compared sequences. Native PRO301(SEQ ID NO:119) also has a Blast score of 165 and 29% homology atresidues 60 to 255 of FIG. 44 with HS46KDA_(—)1, a human coxsackie andadenovirus receptor protein, also known as cell surface protein HCAR.This region of PRO301 also shows a similar Blast score and homology withHSU90716_(—)1. Expression of such proteins is usually associated withviral infection and therapeutics for the prevention of such infectionmay be accordingly conceived. As mentioned in the Background, theexpression of viral receptors is often associated with neoplastictumors.

Therapeutic uses for the PRO234 polypeptides of the invention includestreatments associated with leukocyte homing or the interaction betweenleukocytes and the endothelium during an inflammatory response. Examplesinclude asthma, rheumatoid arthritis, psoriasis and multiple sclerosis.

Since the PRO231 polypeptide and nucleic acid encoding it possesssequence homology to a putative acid phosphatase and its encodingnucleic acid, probes based upon the PRO231 nucleotide sequence may beemployed to identify other novel phosphatase proteins. Soluble forms ofthe PRO231 polypeptide may be employed as antagonists of membrane boundPRO231 activity both in vitro and in vivo. PRO231 polypeptides may beemployed in screening assays designed to identify agonists orantagonists of the native PRO231 polypeptide, wherein such assays maytake the form of any conventional cell-type or biochemical bindingassay. Moreover, the PRO231 polypeptide may serve as a molecular markerfor the tissues in which the polypeptide is specifically expressed.

PRO229 polypeptides can be fused with peptides of interest to determinewhether the fusion peptide has an increased half-life over the peptideof interest. The PRO229 polypeptides can be used accordingly to increasethe half-life of polypeptides of interest. Portions of PRO229 whichcause the increase in half-life are an embodiment of the inventionherein.

PRO238 can be used in assays which measure its ability to reducesubstrates, including oxygen and Aceyl-CoA, and particularly, measurePRO238's ability to produce oxygen free radicals. This is done by usingassays which have been previously described. PRO238 can further be usedto assay for candidates which block, reduce or reverse its reducingabilities. This is done by performing side by side assays wherecandidates are added in one assay having PRO238 and a substrate toreduce, and not added in another assay, being the same but for the lackof the presence of the candidate.

PRO233 polypeptides and portions thereof which have homology toreductase may also be useful for in vivo therapeutic purposes, as wellas for various other applications. The identification of novel reductaseproteins and related molecules may be relevant to a number of humandisorders such as inflammatory disease, organ failure, atherosclerosis,cardiac injury, infertility, birth defects, premature aging, AIDS,cancer, diabetic complications and mutations in general. Given thatoxygen free radicals and antioxidants appear to play important roles ina number of disease processes, the identification of new reductaseproteins and reductase-like molecules is of special importance in thatsuch proteins may serve as potential therapeutics for a variety ofdifferent human disorders. Such polypeptides may also play importantroles in biotechnological and medical research, as well as variousindustrial applications. As a result, there is particular scientific andmedical interest in new molecules, such as PRO233.

The PRO223 polypeptides of the present invention which exhibit serinecarboxypeptidease activity may be employed in vivo for therapeuticpurposes as well as for in vitro purposes. Those of ordinary skill inthe art will well know how to employ PRO223 polypeptides for such uses.

PRO235 polypeptides and portions thereof which may be involved in celladhesion are also useful for in vivo therapeutic purposes, as well asfor various in vitro applications. In addition, PRO235 polypeptides andportions thereof may have therapeutic applications in disease stateswhich involve cell adhesion. Given the physiological importance of celladhesion mechanisms in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in cell adhesion.Therefore, peptides having homology to plexin are of particular interestto the scientific and medical communities.

Because the PRO236 and PRO262 polypeptides disclosed herein arehomologous to various known β-galactosidase proteins, the PRO236 andPRO262 polypeptides disclosed herein will find use in conjugates ofmonoclonal antibodies and the polypeptide for specific killing of tumorcells by generation of active drug from a galactosylated prodrug (e.g.,the generation of 5-fluorouridine from the prodrugβ-D-galactosyl-5-fluorouridine). The PRO236 and PRO262 polypeptidesdisclosed herein may also find various uses both in vivo and in vitro,wherein those uses will be similar or identical to uses for whichβ-galactosidase proteins are now employed. Those of ordinary skill inthe art will well know how to employ PRO236 and PRO262 polypeptides forsuch uses.

PRO239 polypeptides and portions thereof which have homology to densinmay also be useful for in vivo therapeutic purposes, as well as forvarious in vitro applications. In addition, PRO239 polypeptides andportions thereof may have therapeutic applications in disease stateswhich involve synaptic mechanisms, regeneration or cell adhesion. Giventhe physiological importance of synaptic processes, regeneration andcell adhesion mechanisms in vivo, efforts are currently being undertaken to identify new, native proteins which are involved in synapticmachinery and cell adhesion. Therefore, peptides having homology todensin are of particular interest to the scientific and medicalcommunities.

The PRO260 polypeptides described herein can be used in assays todetermine their relation to fucosidase. In particular, the PRO260polypeptides can be used in assays in determining their ability toremove fucose or other sugar residues from proteoglycans. The PRO260polypeptides can be assayed to determine if they have any functional orlocational similarities as fucosidase. The PRO260 polypeptides can thenbe used to regulate the systems in which they are integral.

PRO263 can be used in assays wherein CD44 antigen is generally used todetermine PRO263 activity relative to that of CD44. The results can beused accordingly.

PRO270 polypeptides and portions thereof which effectreduction-oxidation (redox) state may also be useful for in vivotherapeutic purposes, as well as for various in vitro applications. Morespecifically, PRO270 polypeptides may affect the expression of a largevariety of genes thought to be involved in the pathogenesis of AIDS,cancer, atherosclerosis, diabetic complications and in pathologicalconditions involving oxidative stress such as stroke and inflammation.In addition, PRO270 polypeptides and portions thereof may affect theexpression of a genes which have a role in apoptosis. Therefore,peptides having homology to thioredoxin are particularly desirable tothe scientific and medical communities.

PRO272 polypeptides and portions thereof which possess the ability tobind calcium may also have numerous in vivo therapeutic uses, as well asvarious in vitro applications. Therefore, peptides having homology toreticulocalbin are particularly desirable. Those with ordinary skill inthe art will know how to employ PRO272 polypeptides and portions thereoffor such purposes.

PRO294 polypeptides and portions thereof which have homology to collagenmay also be useful for in vivo therapeutic purposes, as well as forvarious other applications. The identification of novel collagens andcollage-like molecules may have relevance to a number of humandisorders. Thus, the identification of new collagens and collage-likemolecules is of special importance in that such proteins may serve aspotential therapeutics for a variety of different human disorders. Suchpolypeptides may also play important roles in biotechnological andmedical research as well as various industrial applications. Given thelarge number of uses for collagen, there is substantial interest inpolypeptides with homology to the collagen molecule.

PRO295 polypeptides and portions thereof which have homology to integrinmay also be useful for in vivo therapeutic purposes, as well as forvarious other applications. The identification of novel integrins andintegrin-like molecules may have relevance to a number of humandisorders such as modulating the binding or activity of cells of theimmune system. Thus, the identification of new integrins andintegrin-like molecules is of special importance in that such proteinsmay serve as potential therapeutics for a variety of different humandisorders. Such polypeptides may also play important roles inbiotechnological and medical research as well as various industrialapplications. As a result, there is particular scientific and medicalinterest in new molecules, such as PRO295.

As the PRO293 polypeptide is clearly a leucine rich repeat polypeptidehomologue, the peptide can be used in all applications that the knownNLRR-1 and NLRR-2 polypeptides are used. The activity can be comparedbetween these peptides and thus applied accordingly.

The PRO247 polypeptides described herein can be used in assays in whichdensin is used to determine the activity of PRO247 relative to densin orthese other proteins. The results can be used accordingly in diagnosticsand/or therapeutic applications with PRO247.

PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides of the presentinvention which possess protease activity may be employed both in vivofor therapeutic purposes and in vitro. Those of ordinary skill in theart will well know how to employ the PRO302, PRO303, PRO304, PRO307 andPRO343 polypeptides of the present invention for such purposes.

PRO328 polypeptides and portions thereof which have homology to GLIP andCRISP may also be useful for in vivo therapeutic purposes, as well asfor various other applications. The identification of novel GLIP andCRISP-like molecules may have relevance to a number of human disorderswhich involve transcriptional regulation or are over expressed in humantumors. Thus, the identification of new GLIP and CRISP-like molecules isof special importance in that such proteins may serve as potentialtherapeutics for a variety of different human disorders. Suchpolypeptides may also play important roles in biotechnological andmedical research as well as in various industrial applications. As aresult, there is particular scientific and medical interest in newmolecules, such as PRO328.

Uses for PRO335, PRO331 or PRO326 including uses in competitive assayswith LIG-1, ALS and decorin to determine their relative activities. Theresults can be used accordingly. PRO335, PRO331 or PRO326 can also beused in assays where LIG-1 would be used to determine if the sameeffects are incurred.

PRO332 contains GAG repeat (GKEK) at amino acid positions 625-628 inFIG. 108 (SEQ ID NO:310). Slippage in such repeats can be associatedwith human disease. Accordingly, PRO332 can use useful for the treatmentof such disease conditions by gene therapy, i.e. by introduction of agene containing the correct GKEK sequence motif.

Other uses of PRO334 include use in assays in which fibrillin or fibulinwould be used to determine the relative activity of PRO334 to fibrillinor fibulin. In particular, PRO334 can be used in assays which requirethe mechanisms imparted by epidermal growth factor repeats.

Native PRO346 (SEQ ID NO:320) has a Blast score of 230, corresponding to27% homology between amino acid residues 21 to 343 with residues 35 to1040 CGM6_HUMAN, a carcinoembryonic antigen cgm6 precursor. Thishomology region includes nearly all but 2 N-terminal extracellulardomain residues, including an immunoglobulin superfamily homology atresidues 148 to 339 of PRO346 in addition to several transmembraneresidues (340-343). Carcinoembryonic antigen precursor, as explained inthe Background is a tumor-specific antigen, and as such, is a recognizedmarker and therapeutic target for the diagnosis and treatment of coloncancer. The expression of tumor-specific antigens is often associatedwith the progression of neoplastic tissue disorders. Native PRO346 (SEQID NO:320) and P_W06874, a human carcinoembryonic antigen CEA-d have aBlast score of 224 and homology of 28% between residues 2 to 343 and 67to 342, respectively. This homology includes the entire extracellulardomain residues of native PRO346, minus the initiator methionine(residues 2 to 18) as well as several transmembrane residues (340-343).

PRO268 polypeptides which have protein disulfide isomerase activity willbe useful for many applications where protein disulfide isomeraseactivity is desirable including, for example, for use in promotingproper disulfide bond formation in recombinantly produced proteins so asto increase the yield of correctly folded protein. Those of ordinaryskill in the art will readily know how to employ such PRO268polypeptides for such purposes.

PRO330 polypeptides of the present invention which possess biologicalactivity related to that of the prolyl 4-hydroxylase alpha subunitprotein may be employed both in vivo for therapeutic purposes and invitro. Those of ordinary skill in the art will well know how to employthe PRO330 polypeptides of the present invention for such purposes.

Uses of the herein disclosed molecules may also be based upon thepositive functional assay hits disclosed and described below.

F. Anti-PRO Antibodies

The present invention further provides anti-PRO antibodies. Exemplaryantibodies include polyclonal, monoclonal, humanized, bispecific, andheteroconjugate antibodies.

1. Polyclonal Antibodies

The anti-PRO antibodies may comprise polyclonal antibodies. Methods ofpreparing polyclonal antibodies are known to the skilled artisan.Polyclonal antibodies can be raised in a mammal, for example, by one ormore injections of an immunizing agent and, if desired, an adjuvant.Typically, the immunizing agent and/or adjuvant will be injected in themammal by multiple subcutaneous or intraperitoneal injections. Theimmunizing agent may include the PRO polypeptide or a fusion proteinthereof. It may be useful to conjugate the immunizing agent to a proteinknown to be immunogenic in the mammal being immunized. Examples of suchimmunogenic proteins include but are not limited to keyhole limpethemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsininhibitor. Examples of adjuvants which may be employed include Freund'scomplete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A,synthetic trehalose dicorynomycolate). The immunization protocol may beselected by one skilled in the art without undue experimentation.

2. Monoclonal Antibodies

The anti-PRO antibodies may, alternatively, be monoclonal antibodies.Monoclonal antibodies may be prepared using hybridoma methods, such asthose described by Kohler and Milstein, Nature 256:495 (1975). In ahybridoma method, a mouse, hamster, or other appropriate host animal, istypically immunized with an immunizing agent to elicit lymphocytes thatproduce or are capable of producing antibodies that will specificallybind to the immunizing agent. Alternatively, the lymphocytes may beimmunized in vitro.

The immunizing agent will typically include the PRO polypeptide or afusion protein thereof Generally, either peripheral blood lymphocytes(“PBLs”) are used if cells of human origin are desired, or spleen cellsor lymph node cells are used if non-human mammalian sources are desired.The lymphocytes are then fused with an immortalized cell line using asuitable fusing agent, such as polyethylene glycol, to form a hybridomacell [Goding, Monoclonal Antibodies: Principles and Practice, AcademicPress, (1986) pp. 59-103]. Immortalized cell lines are usuallytransformed mammalian cells, particularly myeloma cells of rodent,bovine and human origin. Usually, rat or mouse myeloma cell lines areemployed. The hybridoma cells may be cultured in a suitable culturemedium that preferably contains one or more substances that inhibit thegrowth or survival of the unfused, immortalized cells. For example, ifthe parental cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomastypically will include hypoxanthine, aminopterin, and thymidine (“HATmedium”), which substances prevent the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently,support stable high level expression of antibody by the selectedantibody-producing cells, and are sensitive to a medium such as HATmedium. More preferred immortalized cell lines are murine myeloma lines,which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur etal., Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63].

The culture medium in which the hybridoma cells are cultured can then beassayed for the presence of monoclonal antibodies directed against PRO.Preferably, the binding specificity of monoclonal antibodies produced bythe hybridoma cells is determined by immunoprecipitation or by an invitro binding assay, such as radioimmunoassay (RIA) or enzyme-linkedimmunoabsorbent assay (ELISA). Such techniques and assays are known inthe art. The binding affinity of the monoclonal antibody can, forexample, be determined by the Scatchard analysis of Munson and Pollard,Anal. Biochem., 107:220 (1980).

After the desired hybridoma cells are identified, the clones may besubcloned by limiting dilution procedures and grown by standard methods[Goding, supra]. Suitable culture media for this purpose include, forexample, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.Alternatively, the hybridoma cells may be grown in vivo as ascites in amammal.

The monoclonal antibodies secreted by the subclones may be isolated orpurified from the culture medium or ascites fluid by conventionalimmunoglobulin purification procedures such as, for example, proteinA-Sepharose, hydroxylapatite chromatography, gel electrophoresis,dialysis, or affinity chromatography.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies). The hybridoma cells of theinvention serve as a preferred source of such DNA. Once isolated, theDNA may be placed into expression vectors, which are then transfectedinto host cells such as simian COS cells, Chinese hamster ovary (CHO)cells, or myeloma cells that do not otherwise produce immunoglobulinprotein, to obtain the synthesis of monoclonal antibodies in therecombinant host cells. The DNA also may be modified, for example, bysubstituting the coding sequence for human heavy and light chainconstant domains in place of the homologous murine sequences [U.S. Pat.No. 4,816,567; Morrison et al., supra] or by covalently joining to theimmunoglobulin coding sequence all or part of the coding sequence for anon-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptidecan be substituted for the constant domains of an antibody of theinvention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

The antibodies may be monovalent antibodies. Methods for preparingmonovalent antibodies are well known in the art. For example, one methodinvolves recombinant expression of immunoglobulin light chain andmodified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues are substituted withanother amino acid residue or are deleted so as to prevent crosslinking.

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly, Fabfragments, can be accomplished using routine techniques known in theart.

3. Human and Humanized Antibodies

The anti-PRO antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeye et al., Science, 239:1534-1536 (1988)], bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

Human antibodies can also be produced using various techniques known inthe art, including phage display libraries [Hoogenboom and Winter, J.Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581(1991)]. The techniques of Cole et al. and Boerner et al. are alsoavailable for the preparation of human monoclonal antibodies (Cole etal., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly,human antibodies can be made by introducing of human immunoglobulin lociinto transgenic animals, e.g., mice in which the endogenousimmunoglobulin genes have been partially or completely inactivated. Uponchallenge, human antibody production is observed, which closelyresembles that seen in humans in all respects, including generearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the followingscientific publications: Marks et al, Bio/Technology 10, 779-783 (1992);Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368, 812-13(1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996);Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar,Intern. Rev. Immunol. 13 65-93 (1995).

4. Bispecific Antibodies

Bispecific antibodies are monoclonal., preferably human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forthe PRO, the other one is for any other antigen, and preferably for acell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities [Milsteinand Cuello, Nature 305:537-539 (1983)]. Because of the random assortmentof immunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of ten different antibody molecules, ofwhich only one has the correct bispecific structure. The purification ofthe correct molecule is usually accomplished by affinity chromatographysteps. Similar procedures are disclosed in WO 93/08829, published May13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

According to another approach described in WO 96/27011, the interfacebetween a pair of antibody molecules can be engineered to maximize thepercentage of heterodimers which are recovered from recombinant cellculture. The preferred interface comprises at least a part of the CH3region of an antibody constant domain. In this method, one or more smallamino acid side chains from the interface of the first antibody moleculeare replaced with larger side chains (e.g. tyrosine or tryptophan).Compensatory “cavities” of identical or similar size to the large sidechain(s) are created on the interface of the second antibody molecule byreplacing large amino acid side chains with smaller ones (e.g. alanineor threonine). This provides a mechanism for increasing the yield of theheterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies orantibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniques forgenerating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared can be prepared using chemical linkage. Brennan et al., Science229:81 (1985) describe a procedure wherein intact antibodies areproteolytically cleaved to generate F(ab′)₂ fragments. These fragmentsare reduced in the presence of the dithiol complexing agent sodiumarsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

Fab′ fragments may be directly recovered from E. coli and chemicallycoupled to form bispecific antibodies. Shalaby et al., J. Exp. Med.175:217-225 (1992) describe the production of a fully humanizedbispecific antibody F(ab′)₂ molecule. Each Fab′ fragment was separatelysecreted from E. coli and subjected to directed chemical coupling invitro to form the bispecific antibody. The bispecific antibody thusformed was able to bind to cells overexpressing the ErbB2 receptor andnormal human T cells, as well as trigger the lytic activity of humancytotoxic lymphocytes against human breast tumor targets.

Various technique for making and isolating bispecific antibody fragmentsdirectly from recombinant cell culture have also been described. Forexample, bispecific antibodies have been produced using leucine zippers.Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipperpeptides from the Fos and Jun proteins were linked to the Fab′ portionsof two different antibodies by gene fusion. The antibody homodimers werereduced at the hinge region to form monomers and then re-oxidized toform the antibody heterodimers. This method can also be utilized for theproduction of antibody homodimers. The “diabody” technology described byHollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) hasprovided an alternative mechanism for making bispecific antibodyfragments. The fragments comprise a heavy-chain variable domain (V_(H))connected to a light-chain variable domain (V_(L)) by a linker which istoo short to allow pairing between the two domains on the same chain.Accordingly, the V_(H) and V_(L) domains of one fragment are forced topair with the complementary V_(L) and V_(H) domains of another fragment,thereby forming two antigen-binding sites. Another strategy for makingbispecific antibody fragments by the use of single-chain Fv (sFv) dimershas also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).

Antibodies with more than two valencies are contemplated. For example,trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60(1991).

Exemplary bispecific antibodies may bind to two different epitopes on agiven PRO polypeptide herein. Alternatively, an anti-PRO polypeptide armmay be combined with an arm which binds to a triggering molecule on aleukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, orB7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32)and FcγRRIII (CD16) so as to focus cellular defense mechanisms to thecell expressing the particular PRO polypeptide. Bispecific antibodiesmay also be used to localize cytotoxic agents to cells which express aparticular PRO polypeptide. These antibodies possess a PRO-binding armand an arm which binds a cytotoxic agent or a radionuclide chelator,such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody ofinterest binds the PRO polypeptide and further binds tissue factor (TF).

5. Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the presentinvention. Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed totarget immune system cells to unwanted cells [U.S. Pat. No. 4,676,980],and for treatment of HV infection [WO 91/00360; WO 92/200373; EP 03089].It is contemplated that the antibodies may be prepared in vitro usingknown methods in synthetic protein chemistry, including those involvingcrosslinking agents. For example, immunotoxins may be constructed usinga disulfide exchange reaction or by forming a thioether bond. Examplesof suitable reagents for this purpose include iminothiolate andmethyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S.Pat. No. 4,676,980.

6. Effector Function Engineering

It may be desirable to modify the antibody of the invention with respectto effector function, so as to enhance, e.g., the effectiveness of theantibody in treating cancer. For example, cysteine residue(s) may beintroduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedmay have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176:1191-1195 (1992)and Shopes, J. Immunol., 148:2918-2922 (1992). Homodimeric antibodieswith enhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53:2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and may thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3:219-230 (1989).

7. Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibodyconjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin(e.g., an enzymatically active toxin of bacterial, fungal, plant, oranimal origin, or fragments thereof), or a radioactive isotope (i.e., aradioconjugate).

Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPH, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹¹³In, ⁹⁰Y,and ¹⁸⁶Re.

Conjugates of the antibody and cytotoxic agent are made using a varietyof bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238:1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94111026.

In another embodiment, the antibody may be conjugated to a “receptor”(such streptavidin) for utilization in tumor pretargeting wherein theantibody-receptor conjugate is administered to the patient, followed byremoval of unbound conjugate from the circulation using a clearing agentand then administration of a “ligand” (e.g., avidin) that is conjugatedto a cytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82:3688 (1985); Hwang et al., Proc. Natl Acad.Sci. USA, 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

Particularly useful liposomes can be generated by the reverse-phaseevaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257:286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a PRO polypeptide identified herein, aswell as other molecules identified by the screening assays disclosedhereinbefore, can be administered for the treatment of various disordersin the form of pharmaceutical compositions.

If the PRO polypeptide is intracellular and whole antibodies are used asinhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad.Sci. USA, 90:7889-7893 (1993). The formulation herein may also containmore than one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities that donot adversely affect each other. Alternatively, or in addition, thecomposition may comprise an agent that enhances its function, such as,for example, a cytotoxic agent, cytokine, chemotherapeutic agent, orgrowth-inhibitory agent. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsules prepared,for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles, andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, supra.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and yethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated antibodies remainin the body for a long time, they may denature or aggregate as a resultof exposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in immunogenicity. Rational strategies canbe devised for stabilization depending on the mechanism involved. Forexample, if the aggregation mechanism is discovered to be intermolecularS—S bond formation through thio-disulfide interchange, stabilization maybe achieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

G. Uses for anti-PRO Antibodies

The anti-PRO antibodies of the invention have various utilities. Forexample, anti-PRO antibodies may be used in diagnostic assays for PRO,e.g., detecting its expression in specific cells, tissues, or serum.Various diagnostic assay techniques known in the art may be used, suchas competitive binding assays, direct or indirect sandwich assays andimmunoprecipitation assays conducted in either heterogeneous orhomogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques,CRC Press, Inc. (1987) pp. 147-158]. The antibodies used in thediagnostic assays can be labeled with a detectable moiety. Thedetectable moiety should be capable of producing, either directly orindirectly, a detectable signal. For example, the detectable moiety maybe a radioisotope, such as ³H, ¹⁴C, ³²p, ³⁵S, or ¹²⁵I, a fluorescent orchemiluminescent compound, such as fluoresein isothiocyanate, rhodamine,or luciferin, or an enzyme, such as alkaline phosphatase,beta-galactosidase or horseradish peroxidase. Any method known in theart for conjugating the antibody to the detectable moiety may beemployed, including those methods described by Hunter et al., Nature,144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al.,J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. andCytochem., 30:407 (1982).

Anti-PRO antibodies also are useful for the affinity purification of PROfrom recombinant cell culture or natural sources. In this process, theantibodies against PRO are immobilized on a suitable support, such aSephadex resin or filter paper, using methods well known in the art. Theimmobilized antibody then is contacted with a sample containing the PROto be purified, and thereafter the support is washed with a suitablesolvent that will remove substantially all the material in the sampleexcept the PRO, which is bound to the immobilized antibody. Finally, thesupport is washed with another suitable solvent that will release thePRO from the antibody.

The following examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

All patent and literature references cited in the present specificationare hereby incorporated by reference in their entirety.

EXAMPLES

Commercially available reagents referred to in the examples were usedaccording to manufacturer's instructions unless otherwise indicated. Thesource of those cells identified in the following examples, andthroughout the specification, by ATCC accession numbers is the AmericanType Culture Collection, Rockville, Md.

Example 1 Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

The extracellular domain (ECD) sequences (including the secretion signalsequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public databases (e.g., Dayhoff, GenBank), andproprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST2 (Altschul, and Gish, Methods in Enzymology 266:460-80 (1996); asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons with a Blast score of 70 (or insome cases 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.).

Using this extracellular domain homology screen, consensus DNA sequenceswere assembled relative to the other identified EST sequences. Inaddition, the consensus DNA sequences obtained were often (but notalways) extended using repeated cycles of BLAST and phrap to extend theconsensus sequence as far as possible using the sources of EST sequencesdiscussed above.

Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCR acDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for a PROpolypeptide. Forward (.f) and reverse (.r) PCR primers generally rangefrom 20 to 30 nucleotides and are often designed to give a PCR productof about 100-1000 bp in length. The probe (.p) sequences are typically40-55 bp in length. In some cases, additional oligonucleotides aresynthesized when the consensus sequence is greater than about 1-1.5kbp.In order to screen several libraries for a full-length clone, DNA fromthe libraries was screened by PCR amplification, as per Ausubel et al.,Current Protocols in Molecular Biology, with the PCR primer pair. Apositive library was then used to isolate clones encoding the gene ofinterest using the probe oligonucleotide and one of the primer pairs.

The cDNA libraries used to isolate the cDNA clones were constructed bystandard methods using commercially available reagents such as thosefrom Invitrogen, San Diego, Calif. The cDNA was primed with oligo dTcontaining a NotI site, linked with blunt to SalI hemikinased adaptors,cleaved with NotI, sized appropriately by gel electrophoresis, andcloned in a defined orientation into a suitable cloning vector (such aspRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain theSfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in theunique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones Encoding PRO211 and PRO217

Consensus DNA sequences were assembled as described in Example 1 aboveand were designated as DNA28730 and DNA28760, respectively. Based onthese consensus sequences, oligonucleotides were synthesized and used toidentify by PCR a cDNA library that contained the sequences of interestand for use as probes to isolate a clone of the full-length codingsequence for the PRO211 and PRO217 polypeptides. The libraries used toisolate DNA32292-1131 and DNA33094-1131 were fetal lung libraries.

cDNA clones were sequenced in their entirety. The entire nucleotidesequences of PRO211 (DNA32292-1131) and PRO217 (UNQ191) are shown inFIG. 1 (SEQ ID NO:1) and FIG. 3 (SEQ ID NO:3), respectively. Thepredicted polypeptides are 353 and 379 amino acid in length,respectively, with respective molecular weights of approximately 38,190and 41,520 daltons.

The oligonucleotide sequences used in the above procedures were thefollowing:

28730.p (OLI 516) 5′-AGGGAGCACGGACAGTGTGCAGATGTGGACGA- (SEQ ID NO:5)GTGCTCACTAGCA-3′ 28730.f (OLI 517) 5′-AGAGTGTATCTCTGGCTACGC-3′ (SEQ IDNO:6) 28730.r (OLI 518) 5′-TAAGTCCGGCACATTACAGGTC-3′ (SEQ ID NO:7)28760.p (OLI 617) 5′-CCCACGATGTATGAATGGTGGACTTTGTGTGA- (SEQ ID NO:8)CTCCTGGTTTCTGCATC-3′ 28760.f (OLI 618) 5′-AAAGACGCATCTGCGAGTGTCC-3′ (SEQID NO:9) 28760.r (OLI 619) 5′-TGCTGATTTCACACTGCTCTCCC-3′ (SEQ ID NO:10)

Example 3 Isolation of cDNA Clones Encoding Human PRO230

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30857. An EST proprietary toGenentech was employed in the consensus assembly. The EST is designatedas DNA20088 and has the nucleotide sequence shown in FIG. 7 (SEQ IDNO:13).

Based on the DNA30857 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO230.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCGAGGCCTCTGAGAAGTGGCCC-3′ (SEQ ID NO:14) reversePCR primer 5′-GGCGGTATCTCTCTGGCCTCCC-3′ (SEQ ID NO:15)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30857 sequence which had the followingnucleotide sequence

hybridization probe5′-TTCTCCACAGCAGCTGTGGCATCCGATCGTGTCTCAATCCATTCTCTGGG-3′ (SEQ ID NO:16)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO230 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO230 (herein designated asDNA33223-1136 and the derived protein sequence for PRO230.

The entire nucleotide sequence of DNA33223-1136 is shown in FIG. 5 (SEQID NO:11). Clone DNA33223-1136 contains a single open reading frame withan apparent translational initiation site at nucleotide positions100-103 and ending at the stop codon at nucleotide positions 1501-1503(FIG. 5; SEQ ID NO:11). The predicted polypeptide precursor is 467 aminoacids long (FIG. 6).

Example 4 Isolation of cDNA Clones Encoding Human PRO232

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30935. Based on the DNA30935consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO232.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGCTGTGCTACTCCTGCAAAGCCC-3′ (SEQ ID NO:19) reversePCR primer 5′-TGCACAAGTCGGTGTCACAGCACG-3′ (SEQ ID NO:20)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30935 sequence which had the followingnucleotide sequence

hybridization probe 5′-AGCAACGAGGACTGCCTGCAGGTGGAGAACTGCACCCAGCTGGG-3′(SEQ ID NO:21)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO232 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO232 [herein designated as DNA34435-1140]and the derived protein sequence for PRO232.

The entire nucleotide sequence of DNA34435-1140 is shown in FIG. 8 (SEQID NO:17). Clone DNA34435-1140 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 17-19and ending at the stop codon at nucleotide positions 359-361 (FIG. 8;SEQ ID NO:17). The predicted polypeptide precursor is 114 amino acidslong (FIG. 9). Clone DNA34435-1140 has been deposited with ATCC on Sep.16, 1997 and is assigned ATCC deposit no. ATCC 209250.

Analysis of the amino acid sequence of the full-length PRO232 suggeststhat it possesses 35% sequence identity with a stem cell surface antigenfrom Gallus gallus.

Example 5 Isolation of cDNA Clones Encoding PRO187

A proprietary expressed sequence tag (EST) DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST(#843193) was identified which showed homology to fibroblast growthfactor (FGF-8) also known as androgen-induced growth factor. mRNA wasisolated from human fetal lung tissue using reagents and protocols fromInvitrogen, San Diego, Calif. (Fast Track 2). The cDNA libraries used toisolate the cDNA clones were constructed by standard methods usingcommercially available reagents (e.g., Invitrogen, San Diego, Calif.,Life Technologies, Gaithersburg, Md.). The cDNA was primed with oligo dTcontaining a NotI site, linked with blunt to SalI hemikinased adaptors,cleaved with NotI, sized appropriately by gel electrophoresis, andcloned in a defined orientation into the cloning vector pRK5D usingreagents and protocols from Life Technologies, Gaithersburg, Md. (SuperScript Plasmid System). The double-stranded cDNA was sized to greaterthan 1000 bp and the SalI/NotI Tinkered cDNA was cloned into XhoI/NotIcleaved vector. pRK5D is a cloning vector that has an sp6 transcriptioninitiation site followed by an SfiI restriction enzyme site precedingthe XhoI/NotI cDNA cloning sites.

Several libraries from various tissue sources were screened by PCRamplification with the following oligonucleotide probes:

IN843193.f (OLI315) 5′-CAGTACGTGAGGGACCAGGGCGCCATGA-3′ (SEQ ID NO:24)IN843193.r (OLI 317) 5′-CCGGTGACCTGCACGTGCTTGCCA-3′ (SEQ ID NO:25)

A positive library was then used to isolate clones encoding the PRO187gene using one of the above oligonucleotides and the followingoligonucleotide probe:

IN843193.p (OLI 316) 5′-GCGGATCTGCCGCCTGCTCANCTGGTCGGTCATGGCGCCCT-3′(SEQ ID NO:26)

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof PRO187 (DNA27864-1155) is shown in FIG. 10 (SEQ ID NO:22). CloneDNA27864-1155 contains a single open reading frame with an apparenttranslational initiation site at nucleotide position 1 (FIG. 10; SEQ IDNO:22). The predicted polypeptide precursor is 205 amino acids long.Clone DNA27864-1155 has been deposited with the ATCC (designation:DNA27864-1155) and is assigned ATCC deposit no. ATCC 209375.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGNcomputer program) of the full-length sequence, the PRO187 polypeptideshows 74% amino acid sequence identity (Blast score 310) to humanfibroblast growth factor-8 (androgen-induced growth factor).

Example 6 Isolation of cDNA Clones Encoding PRO265

A consensus DNA sequence was assembled relative to other EST sequencesas described in Example 1 above using phrap. This consensus sequence isherein designated DNA33679. Based on the DNA33679 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO265.

PCR primers (two forward and one reverse) were synthesized:

forward PCR primer A: 5′-CGGTCTACCTGTATGGCAACC-3′ (SEQ ID NO:29);forward PCR primer B: 5′-GCAGGACAACCAGATAAACCAC-3′ (SEQ ID NO:30);reverse PCR primer 5′-ACGCAGATTTGAGAAGGCTGTC-3′ (SEQ ID NO:31)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA33679 sequence which had the followingnucleotide sequence

hybridization probe 5′-TTCACGGGCTGCTCTTGCCCAGCTCTTGAAGCTTGAAGAGCTGCAC-3′(SEQ ID NO:32)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with PCRprimer pairs identified above. A positive library was then used toisolate clones encoding the PRO265 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human afetal brain library.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO265 [herein designated as DNA36350-1158](SEQ ID NO:27) and the derived protein sequence for PRO265.

The entire nucleotide sequence of DNA36350-1158 is shown in FIG. 12 (SEQID NO:27). Clone DNA36350-1158 contains a single open reading frame withan apparent translational initiation site at nucleotide positions352-354 and ending at the stop codon at positions 2332-2334 (FIG. 12).The predicted polypeptide precursor is 660 amino acids long (FIG. 13).Clone DNA36350-1158 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209378.

Analysis of the amino acid sequence of the full-length PRO265polypeptide suggests that portions of it possess significant homology tothe fibromodulin and the fibromodulin precursor, thereby indicating thatPRO265 may be a novel member of the leucine rich repeat family,particularly related to fibromodulin.

Example 7 Isolation of cDNA Clones Encoding Human PRO219

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28729. Based on the DNA28729 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO219.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTGACCCTGGTTGTGAATACTCC-3′ (SEQ ID NO:35) reversePCR primer 5′-ACAGCCATGGTCTATAGCTTGG-3′ (SEQ ID NO:36)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28729 sequence which had the followingnucleotide sequence

hybridization probe 5′-GCCTGTCAGTGTCCTGAGGGACACGTGCTCCGCAGCGATGGGAAG-3′(SEQ ID NO:37)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO219 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO219 [herein designated as DNA32290-1164](SEQ ID NO:33) and the derived protein sequence for PRO219.

The entire nucleotide sequence of DNA32290-1164 is shown in FIG. 14 (SEQID NO:33). Clone DNA32290-1164 contains a single open reading frame withan apparent translational initiation site at nucleotide positions204-206 and ending at the stop codon at nucleotide positions 2949-2951(FIG. 14). The predicted polypeptide precursor is 915 amino acids long(FIG. 15). Clone DNA32290-1164 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209384.

Analysis of the amino acid sequence of the full-length PRO219polypeptide suggests that portions of it possess significant homology tothe mouse and human matrilin-2 precursor polypeptides.

Example 8 Isolation of cDNA Clones Encoding Human PRO246

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30955. Based on the DNA30955 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO246.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGGGTCTCCAGGAGAAAGACTC-3′ (SEQ ID NO:40) reversePCR primer 5′-ATTGTGGGCCTTGCAGACATAGAC-3′ (SEQ ID NO:41)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30955 sequence which had the followingnucleotide sequence

hybridization probe5′-GGCCACAGCATCAAAACCTTAGAACTCAATGTACTGGTTCCTCCAGCTCC-3′ (SEQ ID NO:42)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO246 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO246 [herein designated asDNA35639-1172] (SEQ ID NO:38) and the derived protein sequence forPRO246.

The entire nucleotide sequence of DNA35639-1172 is shown in FIG. 16 (SEQID NO:38). Clone DNA35639-1172 contains a single open reading frame withan apparent translational initiation site at nucleotide positions126-128 and ending at the stop codon at nucleotide positions 1296-1298(FIG. 16). The predicted polypeptide precursor is 390 amino acids long(FIG. 17). Clone DNA35639-1172 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209396.

Analysis of the amino acid sequence of the full-length PRO246polypeptide suggests that it possess significant homology to the humancell surface protein HCAR, thereby indicating that PRO246 may be a novelcell surface virus receptor.

Example 9 Isolation of cDNA Clones Encoding Human PRO228

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28758. An EST proprietary to Genentech was employedin the consensus assembly. This EST is shown in FIG. 20 (SEQ ID NO:50)and is herein designated as DNA21951.

Based on the DNA28758 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO228.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGTAATGAGCTCCATTACAG-3′ (SEQ ID NO:51) forward PCRprimer 5′-GGAGTAGAAAGCGCATGG-3′ (SEQ ID NO:52) forward PCR primer5′-CACCTGATACCATGAATGGCAG-3′ (SEQ ID NO:53) reverse PCR primer5′-CGAGCTCGAATTAATTCG-3′ (SEQ ID NO:54) reverse PCR primer5′-GGATCTCCTGAGCTCAGG-3′ (SEQ ID NO:55) reverse PCR primer5′-CCTAGTTGAGTGATCCTTGTAAG-3′ (SEQ ID NO:56)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28758 sequence which had the followingnucleotide sequence

hybridization probe5′-ATGAGACCCACACCTCATGCCGCTGTAATCACCTGACACATTTTGCAATT-3′ (SEQ ID NO:57)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO228 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO228 [herein designated as DNA33092-1202](SEQ ID NO:48) and the derived protein sequence for PRO228.

The entire nucleotide sequence of DNA33092-1202 is shown in FIG. 18 (SEQID NO:48). Clone DNA33092-1202 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 24-26of SEQ ID NO:48 and ending at the stop codon after nucleotide position2093 of SEQ ID NO:48. The predicted polypeptide precursor is 690 aminoacids long (FIG. 19). Clone DNA33092-1202 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209420.

Analysis of the amino acid sequence of the full-length PRO228polypeptide suggests that portions of it possess significant homology tothe secretin-related proteins CD97 and EMR1 as well as the secretinmember, latrophilin, thereby indicating that PRO228 may be a new memberof the secretin related proteins.

Example 10 Isolation of cDNA Clones Encoding Human PRO533

The EST sequence accession number AF007268, a murine fibroblast growthfactor (FGF-15) was used to search various public EST databases (e.g.,GenBank, Dayhoff, etc.) The search was performed using the computerprogram BLAST or BLAST2 [Altschul et al., Methods in Enzymology,266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6frame translation of the EST sequences. The search resulted in a hitwith GenBank EST AA220994, which has been identified as stratagene NT2neuronal precursor 937230.

Based on the Genbank EST AA220994 sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence. Forward and reverse PCR primers may rangefrom 20 to 30 nucleotides (typically about 24), and are designed to givea PCR product of 100-1000 bp in length. The probe sequences aretypically 40-55 bp (typically about 50) in length. In order to screenseveral libraries for a source of a full-length clone, DNA from thelibraries was screened by PCR amplification, as per Ausubel et al.,Current Protocols in Molecular Biology, with the PCR primer pair. Apositive library was then used to isolate clones encoding the gene ofinterest using the probe oligonucleotide and one of the PCR primers.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO533 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalretina. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagents(e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA wasprimed with oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of PRO533 is shown in FIG. 21 (SEQ ID NO:58). CloneDNA49435-1219 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 459461 (FIG. 21;SEQ ID NO:58). The predicted polypeptide precursor is 216 amino acidslong. Clone DNA47412-1219 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209480.

Based on a BLAST-2 and FastA sequence alignment analysis of thefull-length sequence, PRO533 shows amino acid sequence identity tofibroblast growth factor (53%).

The oligonucleotide sequences used in the above procedure were thefollowing:

FGF15.forward: 5′-ATCCGCCCAGATGGCTACAATGTGTA-3′ (SEQ ID NO:60);FGF15.probe: 5′-GCCTCCCGGTCTCCCTGAGCAGTGCCAAAC- (SEQ ID NO:61);AGCGGCAGTGTA-3′ FGF15.reverse: 5′-CCAGTCCGGTGACAAGCCCAAA-3′ (SEQ IDNO:62).

Example 11 Isolation of cDNA Clones Encoding Human PRO245

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30954.

Based on the DNA30954 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO245.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCGTTGTGAAGTTAGTGCCCC-3′ (SEQ ID NO:65) reversePCR primer 5′-ACCTGCGATATCCAACAGAATTG-3′ (SEQ ID NO:66)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30954 sequence which had the followingnucleotide sequence

hybridization probe5′-GGAAGAGGATACAGTCACTCTGGAAGTATTAGTGGCTCCAGCAGTTCC-3′ (SEQ ID NO:67)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO245 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO245 [herein designated asDNA35638-1141] and the derived protein sequence for PRO245.

The entire nucleotide sequence of DNA35638-1141 is shown in FIG. 23 (SEQID NO:63). Clone DNA35638-1141 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 89-91and ending at the stop codon at nucleotide positions 1025-1027 (FIG. 23;SEQ ID NO:63). The predicted polypeptide precursor is 312 amino acidslong (FIG. 24). Clone DNA35638-1141 has been deposited with ATCC on Sep.16, 1997 and is assigned ATCC deposit no. ATCC 209265.

Analysis of the amino acid sequence of the full-length PRO245 suggeststhat a portion of it possesses 60% amino acid identity with the humanc-myb protein and, therefore, may be a new member of the transmembraneprotein receptor tyrosine kinase family.

Example 12 Isolation of cDNA Clones Encoding Human PRO220. PRO221 andPRO227

(a) PRO220

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28749. Based on the DNA28749consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO220.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TCACCTGGAGCCTTTATTGGCC-3′ (SEQ ID NO:74) reversePCR primer 5′-ATACCAGCTATAACCAGGCTGCG-3′ (SEQ ID NO:75)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28749 sequence which had the followingnucleotide sequence:

hybridization probe5′-CAACAGTAAGTGGTTTGATGCTCTTCCAAATCTAGAGATTCTGATGATTGGG-3′ (SEQ IDNO:76)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO220 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the EDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO220 [herein designated asDNA32298-1132 and the derived protein sequence for PRO220.

The entire nucleotide sequence of DNA32298-1132 is shown in FIG. 25 (SEQID NO:68). Clone DNA32298-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions480-482 and ending at the stop codon at nucleotide positions 2604-2606(FIG. 25). The predicted polypeptide precursor is 708 amino acids long(FIG. 26). Clone DNA32298-1132 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209257.

Analysis of the amino acid sequence of the full-length PRO220 shows ithas homology to member of the leucine rich repeat protein superfamily,including the leucine rich repeat protein and the neuronal leucine-richrepeat protein 1.

(b) PRO221

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example I above, wherein the consensussequence is designated herein as DNA28756. Based on the DNA28756consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO221.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCATGTGTCTCCTCCTACAAAG-3′ (SEQ ID NO:77) reversePCR primer 5′-GGGAATAGATGTGATCTGATTGG-3′ (SEQ ID NO:78)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28756 sequence which had the followingnucleotide sequence:

hybridization probe5′CACCTGTAGCAATGCAAATCTCAAGGAAATACCTAGAGATCTTCCTCCTG-3′ (SEQ ID NO:79)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO221 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO221 [herein designated asDNA33089-1132 and the derived protein sequence for PRO221.

The entire nucleotide sequence of DNA33089-1132 is shown in FIG. 27 (SEQID NO:70). Clone DNA33089-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions179-181 and ending at the stop codon at nucleotide positions 956-958(FIG. 27). The predicted polypeptide precursor is 259 amino acids long(FIG. 28). PRO221 is believed to have a transmembrane region at aminoacids 206-225. Clone DNA33089-1132 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209262.

Analysis of the amino acid sequence of the full-length PRO221 shows ithas homology to member of the leucine rich repeat protein superfamily,including the SLIT protein.

(c) PRO227

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example I above, wherein the consensussequence is designated herein as DNA28740. Based on the DNA28740consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO227.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGCAACCGCCTGAAGCTCATCC-3′ (SEQ ID NO:80) reversePCR primer 5′-AAGGCGCGGTGAAAGATGTAGACG-3′ (SEQ ID NO:81)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28740 sequence which had the followingnucleotide sequence:

hybridization probe5′GACTACATGTTTCAGGACCTGTACAACCTCAAGTCACTGGAGGTTGGCGA-3′ (SEQ ID NO:82)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO227 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO227 [herein designated asDNA33786-1132 and the derived protein sequence for PRO227.

The entire nucleotide sequence of DNA33786-1132 is shown in FIG. 29 (SEQID NO:72). Clone DNA33786-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 33-35and ending at the stop codon at nucleotide positions 1893-1895 (FIG.29). The predicted polypeptide precursor is 620 amino acids long (FIG.30). PRO227 is believed to have a transmembrane region. CloneDNA33786-1132 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209253.

Analysis of the amino acid sequence of the full-length PRO221 shows ithas homology to member of the leucine rich repeat protein superfamily,including the platelet glycoprotein V precursor and the humanglycoprotein V.

Example 13 Isolation of cDNA Clones Encoding Human PRO258

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28746.

Based on the DNA28746 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO258.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GCTAGGAATTCCACAGAAGCCC-3′ (SEQ ID NO:85) reversePCR primer 5′-AACCTGGAATGTCACCGAGCTG-3′ (SEQ ID NO:86) reverse PCRprimer 5′-CCTAGCACAGTGACGAGGGACTTGGC-3′ (SEQ ID NO:87)

Additionally, synthetic oligonucleotide hybridization probes wereconstructed from the consensus DNA28740 sequence which had the followingnucleotide sequence:

hybridization probe5′-AAGACACAGCCACCCTAAACTGTCAGTCTTCTGGGAGCAAGCCTGCAGCC-3′ (SEQ ID NO:88)5′-GCCCTGGCAGACGAGGGCGAGTACACCTGCTCAATCTTCACTATGCCTGT-3′ (SEQ ID NO:89)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO258 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO258 [herein designated asDNA35918-1174] (SEQ ID NO:83) and the derived protein sequence forPRO258.

The entire nucleotide sequence of DNA35918-1174 is shown in FIG. 31 (SEQID NO:83). Clone DNA35918-1174 contains a single open reading frame withan apparent translational initiation site at nucleotide positions147-149 of SEQ ID NO:83 and ending at the stop codon after nucleotideposition 1340 of SEQ ID NO:83 (FIG. 31). The predicted polypeptideprecursor is 398 amino acids long (FIG. 32). Clone DNA35918-1174 hasbeen deposited with ATCC and is assigned ATCC deposit no. ATCC 209402.

Analysis of the amino acid sequence of the full-length PRO258polypeptide suggests that portions of it possess significant homology tothe CRTAM and the poliovirus receptor and have an Ig domain, therebyindicating that PRO258 is a new member of the Ig superfamily.

Example 14 Isolation of cDNA Clones Encoding Human PRO266

An expressed sequence tag database was searched for ESTs having homologyto SLIT, resulting in the identification of a single EST sequencedesignated herein as T73996. Based on the T73996 EST sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO266.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTTGGATCTGGGCAACAATAAC-3′ (SEQ ID NO:92) reversePCR primer 5′-ATTGTTGTGCAGGCTGAGTTTAAG-3′ (SEQ ID NO:93)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed which had the following nucleotide sequence

hybridization probe 5′-GGTGGCTATACATGGATAGCAATTACCTGGACACGCTGTCCCGGG-3′(SEQ ID NO:94)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO266 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO266 [herein designated asDNA37150-1178] (SEQ ID NO:90) and the derived protein sequence forPRO266.

The entire nucleotide sequence of DNA37150-1178 is shown in FIG. 33 (SEQID NO:90). Clone DNA37150-1178 contains a single open reading frame withan apparent translational initiation site at nucleotide positions167-169 and ending at the stop codon after nucleotide position 2254 ofSEQ ID NO:90. The predicted polypeptide precursor is 696 amino acidslong (FIG. 34). Clone DNA37150-1178 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209401.

Analysis of the amino acid sequence of the full-length PRO266polypeptide suggests that portions of it possess significant homology tothe SLIT protein, thereby indicating that PRO266 may be a novel leucinerich repeat protein.

Example 15 Isolation of cDNA Clones Encoding Human PRO269

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35705. Based on the DNA35705 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO269.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGAAGGAGATGCGATGCCACCTG-3′ (SEQ ID NO:97)forward PCR primer (.f2) 5′-TGACCAGTGGGGAAGGACAG-3′ (SEQ ID NO:98)forward PCR primer (.f3) 5′-ACAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:99)reverse PCR primer (.r1) 5′-TCAGGGACAAGTGGTGTCTCTCCC-3′ (SEQ ID NO:100)reverse PCR primer (.r2) 5′-TCAGGGAAGGAGTGTGCAGTTCTG-3′ (SEQ ID NO:101)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35705 sequence which had the followingnucleotide sequence:

hybridization probe5′-ACAGCTCCCGATCTCAGTTACTTGCATCGCGGACGAAATCGGCGCTCGCT-3′ (SEQ ID NO:102)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO269 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO269 [herein designated as DNA38260-1180](SEQ ID NO:95) and the derived protein sequence for PRO269.

The entire nucleotide sequence of DNA38260-1180 is shown in FIG. 35 (SEQID NO:95). Clone DNA38260-1180 contains a single open reading frame withan apparent translational initiation site at nucleotide positions314-316 and ending at the stop codon at nucleotide positions 1784-1786(FIG. 35; SEQ ID NO:95). The predicted polypeptide precursor is 490amino acids long (FIG. 36). Clone DNA38260-1180 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209397.

Analysis of the amino acid sequence of the full-length PRO269 suggeststhat portions of it possess significant homology to the humanthrombomodulin proteins, thereby indicating that PRO269 may possess oneor more thrombomodulin-like domains.

Example 16 Isolation of cDNA Clones Encoding Human PRO287

A consensus DNA sequence encoding PRO287 was assembled relative to theother identified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28728. Based on theDNA28728 consensus sequence, oligonucleotides were synthesized toidentify by PCR a cDNA library that contained the sequence of interestand for use as probes to isolate a clone of the full-length codingsequence for PRO287.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCGATTCATAGACCTCGAGAGT-3′ (SEQ ID NO:105) reversePCR primer 5′-GTCAAGGAGTCCTCCACAATAC-3′ (SEQ ID NO:106)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28728 sequence which had the followingnucleotide sequence

hybridization probe 5′-GTGTACAATGGCCATGCCAATGGCCAGCGCATTGGCCGCTTCTGT-3′(SEQ ID NO:107)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO287 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO287 [herein designated as DNA39969-1185,SEQ ID NO:103] and the derived protein sequence for PRO287.

The entire nucleotide sequence of DNA39969-1185 is shown in FIG. 37 (SEQID NO:103). Clone DNA39969-1185 contains a single open reading framewith an apparent translational initiation site at nucleotide positions307-309 and ending at the stop codon at nucleotide positions 1552-1554(FIG. 37; SEQ ID NO:103). The predicted polypeptide precursor is 415amino acids long (FIG. 38). Clone DNA39969-1185 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209400.

Analysis of the amino acid sequence of the full-length PRO287 suggeststhat it may possess one or more procollagen C-proteinase enhancerprotein precursor or procollagen C-proteinase enhancer protein-likedomains. Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO287 shows nucleic acid sequence identity toprocollagen C-proteinase enhancer protein precursor and procollagenC-proteinase enhancer protein (47 and 54%, respectively).

Example 17 Isolation of cDNA Clones Encoding Human PRO214

A consensus DNA sequence was assembled using phrap as described inExample 1 above. This consensus DNA sequence is designated herein asDNA28744. Based on this consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO214 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of DNA32286-1191 is shown in FIG. 39 (SEQ ID NO:108).DNA32286-1191 contains a single open reading frame with an apparenttranslational initiation site at nucleotide position 103 (FIG. 39; SEQID NO:108). The predicted polypeptide precursor is 420 amino acids long(SEQ ID NO:109).

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO214 polypeptide shows amino acid sequenceidentity to HT protein and/or Fibulin (49% and 38%, respectively).

The oligonucleotide sequences used in the above procedure were thefollowing:

28744.p (OLI555)5′-CCTGGCTATCAGCAGGTGGGCTCCAAGTGTCTCGATGTGGATGAGTGTGA-3′ (SEQ ID NO:110)28744.f (OLI556) 5′-ATTCTGCGTGAACACTGAGGGC-3′ (SEQ ID NO:111) 28744.r(OLI557) 5′-ATCTGCTTGTAGCCCTCGGCAC-3′ (SEQ ID NO:112)

Example 18 Isolation of cDNA Clones Encoding Human PRO317

A consensus DNA sequence was assembled using phrap as described inExample 1 above, wherein the consensus sequence is herein designated asDNA28722. Based on this consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence. The forward and reverse PCR primers,respectively, synthesized for this purpose were:

5′-AGGACTGCCATAACTTGCCTG (OLI489) (SEQ ID NO:115) and5′-ATAGGAGTTGAAGCAGCGCTGC (OLI490) (SEQ ID NO:116).

The probe synthesized for this purpose was:

5′-TGTGTGGACATAGACGAGTGCCGCTACCGCTACTGCCAGCACCGC (OLI488) (SEQ IDNO:117)

mRNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification, as perAusubel et al., Current Protocols in Molecular Biology (1989), with thePCR primer pair identified above. A positive library was then used toisolate clones containing the PRO317 gene using the probeoligonucleotide identified above and one of the PCR primers.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of DNA33461-1199 (encoding PRO317) is shown in FIG. 41 (SEQ IDNO:113). Clone DNA33461-1199 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 68-70(FIG. 41; SEQ ID NO:113). The predicted polypeptide precursor is 366amino acids long. The predicted signal sequence is amino acids 1-18 ofFIG. 42 (SEQ ID NO:114). There is one predicted N-linked glycosylationsite at amino acid residue 160. Clone DNA33461-1199 has been depositedwith ATCC and is assigned ATCC deposit no. ATCC 209367.

Based on BLAST™ and FastA™ sequence alignment analysis (using theALIGNT™ computer program) of the full-length PRO317 sequence, PRO317shows the most amino acid sequence identity to EBAF-1 (92%). The resultsalso demonstrate a significant homology between human PRO317 and mouseLEFTY protein. The C-terminal end of the PRO317 protein contains manyconserved sequences consistent with the pattern expected of a member ofthe TGF- superfamily.

In situ expression analysis in human tissues performed as describedbelow evidences that there is distinctly strong expression of the PRO317polypeptide in pancreatic tissue.

Example 19 Isolation of cDNA clones Encoding Human PRO301

A consensus DNA sequence designated herein as DNA35936 was assembledusing phrap as described in Example 1 above. Based on this consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO301 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of native sequence PRO301 is shown in FIG. 43 (SEQ ID NO:118).Clone DNA40628-1216 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 52-54(FIG. 43; SEQ ID NO:118). The predicted polypeptide precursor is 299amino acids long with a predicted molecular weight of 32,583 daltons andpI of 8.29. Clone DNA40628-1216 has been deposited with ATCC and isassigned ATCC deposit No. ATCC 209432.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO301 shows amino acid sequence identity to A33antigen precursor (30%) and coxsackie and adenovirus receptor protein(29%).

The oligonucleotide sequences used in the above procedure were thefollowing:

OLI2162 (35936.f1) 5′-TCGCGGAGCTGTGTTCTGTTTCCC-3′ (SEQ ID NO:120)OLI2163 (35936.p1)5′-TGATCGCGATGGGGACAAAGGCGCAAGCTCGAGAGGAAACTGTTGTGCCT-3′ (SEQ ID NO:121)OLI2164 (35936.f2) 5′-ACACCTGGTTCAAAGATGGG-3′ (SEQ ID NO:122) OLI2165(35936.r1) 5′-TAGGAAGAGTTGCTGAAGGCACGG-3′ (SEQ ID NO:123) OLI2166(35936.f3) 5′-TTGCCTTACTCAGGTGCTAC-3′ (SEQ ID NO:124) OLI2167 (35936.r2)5′-ACTCAGCAGTGGTAGGAAAG-3′ (SEQ ID NO:125)

Example 20 Isolation of cDNA Clones Encoding Human PRO224

A consensus DNA sequence assembled relative to the other identified ESTsequences as described in Example 1, wherein the consensus sequence isdesignated herein as DNA30845. Based on the DNA30845 consensus sequence,oligonucleotides were synthesized to identify by PCR a cDNA library thatcontained the sequence of interest and for use as probes to isolate aclone of the full-length coding sequence for PRO224.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AAGTTCCAGTGCCGCACCAGTGGC-3′ (SEQ ID NO:128)reverse PCR primer 5′-TTGGTTCCACAGCCGAGCTCGTCG-3′ (SEQ ID NO:129)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30845 sequence which had the followingnucleotide sequence

hybridization probe5′-GAGGAGGAGTGCAGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCACC-3′ (SEQ ID NO:130)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO224 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO224 [herein designated as DNA33221-1133]and the derived protein sequence for PRO224.

The entire nucleotide sequence of DNA33221-1133 is shown in FIG. 45 (SEQID NO:126). Clone DNA33221-1133 contains a single open reading framewith an apparent translational initiation site at nucleotide positions33-35 and ending at the stop codon at nucleotide positions 879-899 (FIG.45; SEQ ID NO:126). The start of a transmembrane region begins atnucleotide position 777. The predicted polypeptide precursor is 282amino acids long (FIG. 46). Clone DNA33221-1133 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209263.

Analysis of the amino acid sequence of the full-length PRO224 suggeststhat it has homology to very low-density lipoprotein receptors,apolipoprotein E receptor and chicken oocyte receptors P95. Based on aBLAST and FastA sequence alignment analysis of the full-length sequence,PRO224 has amino acid identity to portions of these proteins in therange from 28% to 45%, and overall identity with these proteins in therange from 33% to 39%.

Example 21 Isolation of cDNA Clones Encoding Human PRO222

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28771. Based on the DNA28771consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO222.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCTCCTATCGCTGCTTCCCGG-3′ (SEQ ID NO:133) reversePCR primer 5′-AGCCAGGATCGCAGTAAAACTCC-3′ (SEQ ID NO:134)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28771 sequence which had the followingnucleotide sequence:

hybridization probe5′-ATTTAAACTTGATGGGTCTGCGTATCTTGAGTGCTTACAAAACCTTATCT-3′ (SEQ ID NO:135)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO222 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO222 [herein designated as DNA33107-1135]and the derived protein sequence for PRO222.

The entire nucleotide sequence of DNA33107-1135 is shown in FIG. 47 (SEQID NO:131). Clone DNA33107-1135 contains a single open reading framewith an apparent translational initiation site at nucleotide positions159-161 and ending at the stop codon at nucleotide positions 1629-1631(FIG. 47; SEQ ID NO:131). The predicted polypeptide precursor is 490amino acids long (FIG. 48). Clone DNA33107-1135 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209251.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO222 shows amino acid sequence identity to mousecomplement factor h precursor (25-26%), complement receptor (27-29%),mouse complement C3b receptor type 2 long form precursor (2547%) andhuman hypothetical protein kiaa0247 (40%).

Example 22 Isolation of cDNA clones Encoding PRO234

A consensus DNA sequence was assembled (DNA30926) using phrap asdescribed in Example 1 above. Based on this consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence.

RNA for the construction of the cDNA libraries was isolated usingstandard isolation protocols, e.g., Ausubel et al., Current Protocols inMolecular Biology, from tissue or cell line sources or it was purchasedfrom commercial sources (e.g., Clontech). The cDNA libraries used toisolate the cDNA clones were constructed by standard methods (e.g.,Ausubel et al.) using commercially available reagents (e.g.,Invitrogen). This library was derived from 22 week old fetal braintissue.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of PRO234 is shown in FIG. 49 (SEQ ID NO:136). The predictedpolypeptide precursor is 382 amino acids long and has a calculatedmolecular weight of approximately 43.1 kDa.

The oligonucleotide sequences used in the above procedure were thefollowing:

30926.p (OLI826) (SEQ ID NO:138): 5′-GTTCATTGAAAACCTCTTGCCATCT                 GATGGTGACTTCTGGATTGGGCTCA-3′ 30926.f (OLI827) (SEQ IDNO:139): 5′-AAGCCAAAGAAGCCTGCAGGAGGG-3′ 30926.r (OLI828) (SEQ IDNO:140): 5′-CAGTCCAAGCATAAAGGTCCTGGC-3′

Example 23 Isolation of cDNA Clones Encoding Human PRO231

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence was designated herein as DNA30933. Based on the DNA30933consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO231.

Three PCR primers (two forward and one reverse) were synthesized:

forward PCR primer 1 5′-CCAACTACCAAAGCTGCTGGAGCC-3′ (SEQ ID NO:143)forward PCR primer 2 5′-GCAGCTCTATTACCACGGGAAGGA-3′ (SEQ ID NO:144)reverse PCR primer 5′-TCCTTCCCGTGGTAATAGAGCTGC-3′ (SEQ ID NO:145)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30933 sequence which had the followingnucleotide sequence

hybridization probe 5′-GGCAGAGAACCAGAGGCCGGAGGAGACTGCCTCTTTACAGCCAGG-3′(SEQ ID NO:146)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO231 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO231 [herein designated as DNA34434-1139]and the derived protein sequence for PRO231.

The entire nucleotide sequence of DNA34434-1139 is shown in FIG. 51 (SEQID NO:141). Clone DNA34434-1139 contains a single open reading framewith an apparent translational initiation site at nucleotide positions173-175 and ending at the stop codon at nucleotide positions 1457-1459(FIG. 51; SEQ ID NO:141). The predicted polypeptide precursor is 428amino acids long (FIG. 52). Clone DNA34434-1139 has been deposited withATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209252.

Analysis of the amino acid sequence of the full-length PRO231 suggeststhat it possesses 30% and 31% amino acid identity with the human and ratprostatic acid phosphatase precursor proteins, respectively.

Example 24 Isolation of cDNA Clones Encoding Human PRO229

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28762. Based on the DNA28762 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO229.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCAGCTCATCACCTTCACCTGCC-3′ (SEQ ID NO:149)reverse PCR primer 5′-GGCTCATACAAAATACCACTAGGG-3′ (SEQ ID NO:150)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28762 sequence which had the followingnucleotide sequence

hybridization probe5′-GGGCCTCCACCGCTGTGAAGGGCGGGTGGAGGTGGAACAGAAAGGCCAGT-3′ (SEQ ID NO:151)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO229 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO229 [herein designated as DNA33100-1159](SEQ ID NO:147) and the derived protein sequence for PRO229.

The entire nucleotide sequence of DNA33100-1159 is shown in FIG. 53 (SEQID NO:147). Clone DNA33100-1159 contains a single open reading framewith an apparent translational initiation site at nucleotide positions98-100 and ending at the stop codon at nucleotide positions 1139-1141(FIG. 53). The predicted polypeptide precursor is 347 amino acids long(FIG. 54). Clone DNA33100-1159 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209377

Analysis of the amino acid sequence of the full-length PRO229polypeptide suggests that portions of it possess significant homology toantigen wc1.1, M130 antigen and CD6.

Example 25 Isolation of cDNA Clones Encoding Human PRO238

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described above in Example 1. This consensus sequence isherein designated DNA30908. Based on the DNA30908 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO238.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGTGCTAAACTGGTGCTCTGTGGC-3′ (SEQ ID NO:154)forward PCR primer 2 5′-CAGGGCAAGATGAGCATTCC-3′ (SEQ ID NO:155) reversePCR primer 5′-TCATACTGTTCCATCTCGGCACGC-3′ (SEQ ID NO:156)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30908 sequence which had the followingnucleotide sequence

hybridization probe5′-AATGGTGGGGCCCTAGAAGAGCTCATCAGAGAACTCACCGCTTCTCATGC-3′ (SEQ ID NO:157)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO238 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO238 and the derived protein sequence forPRO238.

The entire nucleotide sequence of DNA35600-1162 is shown in FIG. 55 (SEQID NO:152). Clone DNA35600-1162 contains a single open reading framewith an apparent translational initiation site at nucleotide positions134-136 and ending prior to the stop codon at nucleotide positions1064-1066 (FIG. 55). The predicted polypeptide precursor is 310 aminoacids long (FIG. 56). Clone DNA35600-1162 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209370.

Analysis of the amino acid sequence of the full-length PRO238polypeptide suggests that portions of it possess significant homology toreductase, particularly oxidoreductase, thereby indicating that PRO238may be a novel reductase.

Example 26 Isolation of cDNA Clones Encoding Human PRO233

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performedusing the computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266:460-480 (1996)) as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequence. Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash).

An expressed sequence tag (EST) was identified by the EST databasesearch and a consensus DNA sequence was assembled relative to other ESTsequences using phrap. This consensus sequence is herein designatedDNA30945. Based on the DNA30945 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO233.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-GGTGAAGGCAGAAATTGGAGATG-3′ (SEQ ID NO:160) reversePCR primer 5′-ATCCCATGCATCAGCCTGTTTACC-3′ (SEQ ID NO:161)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30945 sequence which had the followingnucleotide sequence

hybridization probe5′-GCTGGTGTAGTCTATACATCAGATTTGTTTGCTACACAAGATCCTCAG-3′ (SEQ ID NO:162)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO233 gene using the probe oligonucleotide.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO233 [herein designated as DNA34436-1238](SEQ ID NO:158) and the derived protein sequence for PRO233.

The entire nucleotide sequence of DNA34436-1238 is shown in FIG. 57 (SEQID NO:158). Clone DNA34436-1238 contains a single open reading framewith an apparent translational initiation site at nucleotide positions101-103 and ending at the stop codon at nucleotide positions 1001-1003(FIG. 57). The predicted polypeptide precursor is 300 amino acids long(FIG. 58). The full-length PRO233 protein shown in FIG. 58 has anestimated molecular weight of about 32,964 daltons and a pI of about9.52. Clone DNA34436-1238 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209523.

Analysis of the amino acid sequence of the full-length PRO233polypeptide suggests that portions of it possess significant homology toreductase proteins, thereby indicating that PRO233 may be a novelreductase.

Example 27 Isolation of cDNA Clones Encoding Human PRO223

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30836. Based on the DNA30836 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO223.

PCR primer pairs (one forward and two reverse) were synthesized:

forward PCR primer 5′-TTCCATGCCACCTAAGGGAGACTC-3′ (SEQ ID NO:165)reverse PCR primer 1 5′-TGGATGAGGTGTGCAATGGCTGGC-3′ (SEQ ID NO:166)reverse PCR primer 2 5′-AGCTCTCAGAGGCTGGTCATAGGG-3′ (SEQ ID NO:167)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30836 sequence which had the followingnucleotide sequence

hybridization probe5′-GTCGGCCCTTTCCCAGGACTGAACATGAAGAGTTATGCCGGCTTCCTCAC-3′ (SEQ ID NO:168)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO223 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO223 [herein designated as DNA33206-1165](SEQ ID NO:163) and the derived protein sequence for PRO223.

The entire nucleotide sequence of DNA33206-1165 is shown in FIG. 59 (SEQID NO:163). Clone DNA33206-1165 contains a single open reading framewith an apparent translational initiation site at nucleotide positions97-99 and ending at the stop codon at nucleotide positions 1525-1527(FIG. 59). The predicted polypeptide precursor is 476 amino acids long(FIG. 60). Clone DNA33206-1165 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209372.

Analysis of the amino acid sequence of the full-length PRO223polypeptide suggests that it possesses significant homology to variousserine carboxypeptidase proteins, thereby indicating that PRO223 may bea novel serine carboxypeptidase.

Example 28 Isolation of cDNA Clones Encoding Human PRO235

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated “DNA30927”. Based on the DNA30927 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO235.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGGAATACCGCCTCCTGCAG-3′ (SEQ ID NO:171) reversePCR primer 5′-CTTCTGCCCTTTGGAGAAGATGGC-3′ (SEQ ID NO:172)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30927 sequence which had the followingnucleotide sequence

hybridization probe 5′-GGACTCACTGGCCCAGGCCTTCAATATCACCAGCCAGGACGAT-3′(SEQ ID NO:173)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO235 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO235 [herein designated as DNA35558-1167](SEQ ID NO:169) and the derived protein sequence for PRO235.

The entire nucleotide sequence of DNA35558-1167 is shown in FIG. 61 (SEQID NO:169). Clone DNA35558-1167 contains a single open reading framewith an apparent translational initiation site at nucleotide positions667-669 and ending at the stop codon at nucleotide positions 2323-2325(FIG. 61). The predicted polypeptide precursor is 552 amino acids long(FIG. 62). Clone DNA35558-1167 has been deposited with ATCC and isassigned ATCC deposit no. 209374.

Analysis of the amino acid sequence of the full-length PRO235polypeptide suggests that portions of it possess significant homology tothe human, mouse and Xenopus plexin protein, thereby indicating thatPRO235 may be a novel plexin protein.

Example 29 Isolation of cDNA Clones Encoding Human PRO236 and HumanPRO262

Consensus DNA sequences were assembled relative to other EST sequencesusing phrap as described in Example 1 above. These consensus sequencesare herein designated DNA30901 and DNA30847. Based on the DNA30901 andDNA30847 consensus sequences, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO236 and PRO262, respectively.

Based upon the DNA30901 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

forward PCR primer 5′-TGGCTACTCCAAGACCCTGGCATG-3′ (SEQ ID NO:178)reverse PCR primer 5′-TGGACAAATCCCCTTGCTCAGCCC-3′ (SEQ ID NO:179)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30901 sequence which had the followingnucleotide sequence

hybridization probe5′-GGGCTTCACCGAAGCAGTGGACCTTTATTTTGACCACCTGATGTCCAGGG-3′ (SEQ ID NO:180)

Based upon the DNA30847 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

forward PCR primer 5′-CCAGCTATGACTATGATGCACC-3′ (SEQ ID NO:181) reversePCR primer 5′-TGGCACCCAGAATGGTGTTGGCTC-3′ (SEQ ID NO:182)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30847 sequence which had the followingnucleotide sequence

hybridization probe5′-CGAGATGTCATCAGCAAGTTCCAGGAAGTTCCTTTGGGACCTTTACCTCC-3′ (SEQ ID NO:183)

In order to screen several libraries for a source of full-length clones,DNA from the libraries was screened by PCR amplification with the PCRprimer pairs identified above. Positive libraries were then used toisolate clones encoding the PRO236 and PRO262 genes using the probeoligonucleotides and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue for PRO236 and human fetal liver tissue for PRO262.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO236 [herein designated as DNA35599-1168](SEQ ID NO:174), the derived protein sequence for PRO236, thefull-length DNA sequence for PRO262 [herein designated as DNA36992-1168](SEQ ID NO:176) and the derived protein sequence for PRO262.

The entire nucleotide sequence of DNA35599-1168 is shown in FIG. 63 (SEQID NO:174). Clone DNA35599-1168 contains a single open reading framewith an apparent translational initiation site at nucleotide positions69-71 and ending at the stop codon at nucleotide positions 1977-1979(FIG. 63). The predicted polypeptide precursor is 636 amino acids long(FIG. 64). Clone DNA35599-1168 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209373.

The entire nucleotide sequence of DNA36992-1168 is shown in FIG. 65 (SEQID NO:176). Clone DNA36992-1168 contains a single open reading framewith an apparent translational initiation site at nucleotide positions240-242 and ending at the stop codon at nucleotide positions 2202-2204(FIG. 65). The predicted polypeptide precursor is 654 amino acids long(FIG. 66). Clone DNA36992-1168 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209382.

Analysis of the amino acid sequence of the full-length PRO236 and PRO262polypeptides suggests that portions of those polypeptides possesssignificant homology to β-galactosidase proteins derived from varioussources, thereby indicating that PRO236 and PRO262 may be novelβ-galactosidase homologs.

Example 30 Isolation of cDNA Clones Encoding Human PRO239

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30909. Based on the DNA30909 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO239.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCTCCCTCTATTACCCATGTC-3′ (SEQ ID NO:186) reversePCR primer 5′-GACCAACTTTCTCTGGGAGTGAGG-3′ (SEQ ID NO:187)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30909 sequence which had the followingnucleotide sequence

hybridization probe5′-GTCACTTTATTTCTCTAACAACAAGCTCGAATCCTTACCAGTGGCAG-3′ (SEQ ID NO:188)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO239 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO239 [herein designated as DNA34407-1169](SEQ ID NO:184) and the derived protein sequence for PRO239.

The entire nucleotide sequence of DNA34407-1169 is shown in FIG. 67 (SEQID NO:184). Clone DNA34407-1169 contains a single open reading framewith an apparent translational initiation site at nucleotide positions72-74 and ending at the stop codon at nucleotide positions 1575-1577(FIG. 67). The predicted polypeptide precursor is 501 amino acids long(FIG. 68). Clone DNA34407-1169 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209383.

Analysis of the amino acid sequence of the full-length PRO239polypeptide suggests that portions of it possess significant homology tothe densin protein, thereby indicating that PRO239 may be a novelmolecule in the densin family.

Example 31 Isolation of cDNA Clones Encoding Human PRO257

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28731. Based on the DNA28731 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO257.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TCTCTATTCCAAACTGTGGCG-3′ (SEQ ID NO:191) reversePCR primer 5′-TTTGATGACGATTCGAAGGTGG-3′ (SEQ ID NO:192)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28731 sequence which had the followingnucleotide sequence

hybridization probe5′-GGAAGGATCCTTCACCAGCCCCAATTACCCAAAGCCGCATCCTGAGC-3′ (SEQ ID NO:193)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO257 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO257 [herein designated as DNA35841-1173(SEQ ID NO:189) and the derived protein sequence for PRO257.

The entire nucleotide sequence of DNA35841-1173 is shown in FIG. 69 (SEQID NO:189). Clone DNA35841-1173 contains a single open reading framewith an apparent translational initiation site at nucleotide positions964-966 and ending at the stop codon at nucleotide positions 2785-2787(FIG. 69). The predicted polypeptide precursor is 607 amino acids long(FIG. 70). Clone DNA35841-1173 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209403.

Analysis of the amino acid sequence of the full-length PRO257polypeptide suggests that portions of it possess significant homology tothe ebnerin protein, thereby indicating that PRO257 may be a novelprotein member related to the ebnerin protein.

Example 32 Isolation of cDNA Clones Encoding Human PRO260

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30834. Based on the DNA30834 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO260.

PCR primers (forward and two reverse) were synthesized:

forward PCR primer: 5′-TGGTTTGACCAGGCCAAGTTCGG-3′ (SEQ ID NO:196);reverse PCR primer A: 5′-GGATTCATCCTCAAGGAAGAGCGG-3′ (SEQ ID NO:197);and reverse PCR primer B: 5′AACTTGCAGCATCAGCCACTCTGC-3′ (SEQ ID NO:198)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30834 sequence which had the followingnucleotide sequence:

hybridization probe 5′-TTCCGTGCCCAGCTTCGGTAGCGAGTGGTTCTGGTGGTATTGGCA-3′(SEQ ID NO:199)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO260 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO260 [herein designated as DNA33470-1175](SEQ ID NO:194) and the derived protein sequence for PRO260.

The entire nucleotide sequence of DNA33470-1175 is shown in FIG. 71 (SEQID NO:194). Clone DNA33470-1175 contains a single open reading framewith an apparent translational initiation site at nucleotide positions67-69 and ending at the stop codon 1468-1470 (see FIG. 71). Thepredicted polypeptide precursor is 467 amino acids long (FIG. 72). CloneDNA33470-1175 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209398.

Analysis of the amino acid sequence of the full-length PRO260polypeptide suggests that portions of it possess significant homology tothe alpha-1-fucosidase precursor, thereby indicating that PRO260 may bea novel fucosidase.

Example 33 Isolation of cDNA Clones Encoding Human PRO263

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30914. Based on the DNA30914 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO263.

PCR primers (tow forward and one reverse) were synthesized:

forward PCR primer 1: 5′-GAGCTTTCCATCCAGGTGTCATGC-3′ (SEQ ID NO:202);forward PCR primer 2: 5′-GTCAGTGACAGTACCTACTCGG-3′ (SEQ ID NO:203);reverse PCR primer: 5′-TGGAGCAGGAGGAGTAGTAGTAGG-3′ (SEQ ID NO:204)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30914 sequence which had the followingnucleotide sequence:

hybridization probe5′-AGGAGGCCTGTAGGCTGCTGGGACTAAGTTTGGCCGGCAAGGACCAAGTT-3′ (SEQ ID NO:205)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO263 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO263 [herein designated as DNA34431-1177](SEQ ID NO:200) and the derived protein sequence for PRO263.

The entire nucleotide sequence of DNA34431-1177 is shown in FIG. 73 (SEQID NO:200). Clone DNA34431-1177 contains a single open reading framewith an apparent translational initiation site at nucleotide positions160-162 of SEQ ID NO:200 and ending at the stop codon after thenucleotide at position 1126-1128 of SEQ ID NO:200 (FIG. 73). Thepredicted polypeptide precursor is 322 amino acids long (FIG. 74). CloneDNA34431-1177 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209399.

Analysis of the amino acid sequence of the full-length PRO263polypeptide suggests that portions of it possess significant homology toCD44 antigen, thereby indicating that PRO263 may be a novel cell surfaceadhesion molecule.

Example 34 Isolation of cDNA Clones Encoding Human PRO270

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence was designated herein as DNA35712. Based on the DNA35712consensus sequence, oligonucleotides were synthesized: 1) to identify byPCR a cDNA library that contained the sequence of interest, and 2) foruse as probes to isolate a clone of the full-length coding sequence forPRO270. Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCTTGGATATTCGCATGGGCCTAC-3′ (SEQ ID NO:208)forward PCR primer (.f2) 5′-TGGAGACAATATCCCTGAGG-3′ (SEQ ID NO:209)reverse PCR primer (.r1) 5′-AACAGTTGGCCACAGCATGGCAGG-3′ (SEQ ID NO:210)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35712 sequence which had the followingnucleotide sequence

hybridization probe5′-CCATTGATGAGGAACTAGAACGGGACAAGAGGGTCACTTGGATTGTGGAG-3′ (SEQ ID NO:211)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO270 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO270 [herein designated as DNA39510-1181](SEQ ID NO:206) and the derived protein sequence for PRO270.

The entire nucleotide sequence of DNA39510-1181 is shown in FIG. 75 (SEQID NO:206). Clone DNA39510-1181 contains a single open reading framewith an apparent translational initiation site at nucleotide positions3-5 and ending at the stop codon at nucleotide positions 891-893 (FIG.75; SEQ ID NO:206). The predicted polypeptide precursor is 296 aminoacids long (FIG. 76). Clone DNA39510-1181 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209392.

Analysis of the amino acid sequence of the full-length PRO270 suggeststhat portions of it possess significant homology to thethioredoxin-protein, thereby indicating that the PRO270 protein may be anovel member of the thioredoxin family.

Example 35 Isolation of cDNA Clones Encoding Human PRO271

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35737. Based on the DNA35737 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO271.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGCTTCGCTACTGCCCTC-3′ (SEQ ID NO:214) forwardPCR primer 2 5′-TTCCCTTGTGGGTTGGAG-3′ (SEQ ID NO:215) forward PCR primer3 5′-AGGGCTGGAAGCCAGTTC-3′ (SEQ ID NO:216) reverse PCR primer 15′-AGCCAGTGAGGAAATGCG-3′ (SEQ ID NO:217) reverse PCR primer 25′-TGTCCAAAGTACACACACCTGAGG-3′ (SEQ ID NO:218)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35737 sequence which had the followingnucleotide sequence

hybridization probe 5′-GATGCCACGATCGCCAAGGTGGGACAGCTCTTTGCCGCCTGGAAG-3′(SEQ ID NO:219)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO271 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO271 [herein designated as DNA39423-1182](SEQ ID NO:212) and the derived protein sequence for PRO271.

The entire nucleotide sequence of DNA39423-1182 is shown in FIG. 77 (SEQID NO:212). Clone DNA39423-1182 contains a single open reading framewith an apparent translational initiation site at nucleotide positions101-103 and ending at the stop codon at nucleotide positions 1181-1183(FIG. 77). The predicted polypeptide precursor is 360 amino acids long(FIG. 78). Clone DNA39423-1182 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209387.

Analysis of the amino acid sequence of the full-length PRO271polypeptide suggests that it possess significant homology to theproteoglycan link protein, thereby indicating that PRO271 may be a linkprotein homolog.

Example 36 Isolation of cDNA Clones Encoding Human PRO272

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA36460. Based on the DNA36460 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO272.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-CGCAGGCCCTCATGGCCAGG-3′ (SEQ ID NO:222)forward PCR primer (.f2) 5′-GAAATCCTGGGTAATTGG-3′ (SEQ ID NO:223)reverse PCR primer 5′-GTGCGCGGTGCTCACAGCTCATC-3′ (SEQ ID NO:224)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA36460 sequence which had the followingnucleotide sequence

hybridization probe 5′-CCCCCCTGAGCGACGCTCCCCCATGATGACGCCCACGGGAACTTC-3′(SEQ ID NO:225)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO272 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO272 [herein designated as DNA40620-1183](SEQ ID NO:220) and the derived protein sequence for PRO272.

The entire nucleotide sequence of DNA40620-1183 is shown in FIG. 79 (SEQID NO:220). Clone DNA40620-1183 contains a single open reading framewith an apparent translational initiation site at nucleotide positions35-37 and ending at the stop codon at nucleotide positions 1019-1021(FIG. 79). The predicted polypeptide precursor is 328 amino acids long(FIG. 80). Clone DNA40620-1183 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209388.

Analysis of the amino acid sequence of the full-length PRO272polypeptide suggests that portions of it possess significant homology tothe human and mouse reticulocalbin proteins, respectively, therebyindicating that PRO272 may be a novel reticulocalbin protein.

Example 37 Isolation of cDNA Clones Encoding Human PRO294

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35731. Based on the DNA35731 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO294.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGTCTCGCACACCGATC-3′ (SEQ ID NO:228)forward PCR primer (.f2) 5′-CTGCTGTCCACAGGGGAG-3′ (SEQ ID NO:229)forward PCR primer (.f3) 5′-CCTTGAAGCATACTGCTC-3′ (SEQ ID NO:230)forward PCR primer (.f4) 5′-GAGATAGCAATTTCCGCC-3′ (SEQ ID NO:231)reverse PCR primer (.r1) 5′-TTCCTCAAGAGGGCAGCC-3′ (SEQ ID NO:232)reverse PCR primer (.r2) 5′-CTTGGCACCAATGTCCGAGATTTC-3′ (SEQ ID NO:233)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35731 sequence which had the followingnucleotide sequence

hybridization probe 5′-GCTCTGAGGAAGGTGACGCGCGGGGCCTCCGAACCCTTGGCCTTG-3′(SEQ ID NO:234)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO294 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO294 [herein designated asDNA40604-1187] (SEQ ID NO:226) and the derived protein sequence forPRO294.

The entire nucleotide sequence of DNA40604-1187 is shown in FIG. 81 (SEQID NO:226). Clone DNA40604-1187 contains a single open reading framewith an apparent translational initiation site at nucleotide positions396-398 and ending at the stop codon at nucleotide positions 2046-2048(FIG. 81). The predicted polypeptide precursor is 550 amino acids long(FIG. 82). Clone DNA40604-1187 has been deposited with ATCC and isassigned ATCC deposit no. 209394.

Analysis of the amino acid sequence of the full-length PRO294polypeptide suggests that portions of it possess significant homology toportions of various collagen proteins, thereby indicating that PRO294may be collagen-like molecule.

Example 38 Isolation of cDNA Clones Encoding Human PRO295

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35814. Based on the DNA35814 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO295.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCAGAGCGGAGATGCAGCGGCTTG-3′ (SEQ ID NO:238)forward PCR primer (.f2) 5′-CCCAGCATGTACTGCCAG-3′ (SEQ ID NO:239)forward PCR primer (.f3) 5′-TTGGCAGCTTCATGGAGG-3′ (SEQ ID NO:240)forward PCR primer (.f4) 5′-CCTGGGCAAAAATGCAAC-3′ (SEQ ID NO:241)reverse PCR primer (.r1) 5′-CTCCAGCTCCTGGCGCACCTCCTC-3′ (SEQ ID NO:242)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35814 sequence which had the followingnucleotide sequence

hybridization probe 5′-GGCTCTCAGCTACCGCGCAGGAGCGAGGCCACCCTCAATGAGATG-3′(SEQ ID NO:243)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO295 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO295 [herein designated as DNA38268-1188](SEQ ID NO:235) and the derived protein sequence for PRO295.

The entire nucleotide sequence of DNA38268-1188 is shown in FIG. 83 (SEQID NO:235). Clone DNA38268-1188 contains a single open reading framewith an apparent translational initiation site at nucleotide positions153-155 and ending at the stop codon at nucleotide positions 1202-1204(FIG. 83). The predicted polypeptide precursor is 350 amino acids long(FIG. 84). Clone DNA38268-1188 has been deposited with ATCC and isassigned ATCC deposit no. 209421.

Analysis of the amino acid sequence of the full-length PRO295polypeptide suggests that portions of it possess significant homology tothe integrin proteins, thereby indicating that PRO295 may be a novelintegrin.

Example 39 Isolation of cDNA Clones Encoding Human PRO293

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performedusing the computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266:460-480 (1996)) as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequence. Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.

Based on an expression tag sequence designated herein as T08294identified in the above analysis, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of the full-lengthcoding sequence for PRO293.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AACAAGGTAAGATGCCATCCTG-3′ (SEQ ID NO:246) reversePCR primer 5′-AAACTTGTCGATGGAGACCAGCTC-3′ (SEQ ID NO:247)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the expression sequence tag which had the followingnucleotide sequence

hybridization probe 5′-AGGGGCTGCAAAGCCTGGAGAGCCTCTCCTTCTATGACAACCAGC-3′(SEQ ID NO:248)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO293 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO293 [herein designated as DNA37151-1193](SEQ ID NO:244) and the derived protein sequence for PRO293.

The entire nucleotide sequence of DNA37151-1193 is shown in FIG. 85 (SEQID NO:244). Clone DNA37151-1193 contains a single open reading framewith an apparent translational initiation site at nucleotide positions881-883 and ending at the stop codon after nucleotide position 3019 ofSEQ ID NO:244, FIG. 85). The predicted polypeptide precursor is 713amino acids long (FIG. 86). Clone DNA37151-1193 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209393.

Analysis of the amino acid sequence of the full-length PRO293polypeptide suggests that portions of it possess significant homology tothe NLRR proteins, thereby indicating that PRO293 may be a novel NLRRprotein.

Example 40 Isolation of cDNA Clones Encoding Human PRO247

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA33480. Based on the DNA33480 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO247.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CAACAATGAGGGCACCAAGC-3′ (SEQ ID NO:251) reversePCR primer 5′-GATGGCTAGGTTCTGGAGGTTCTG-3′ (SEQ ID NO:252)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the DNA33480 expression sequence tag which had thefollowing nucleotide sequence

hybridization probe5′-CAACCTGCAGGAGATTGACCTCAAGGACAACAACCTCAAGACCATCG-3′ (SEQ ID NO:253)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO247 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO247 [herein designated as DNA35673-1201](SEQ ID NO:249) and the derived protein sequence for PRO247.

The entire nucleotide sequence of DNA35673-1201 is shown in FIG. 89 (SEQID NO:249). Clone DNA35673-1201 contains a single open reading framewith an apparent translational initiation site at nucleotide positions80-82 of SEQ ID NO:249 and ending at the stop codon after nucleotideposition 1717 of SEQ ID NO:249 (FIG. 89). The predicted polypeptideprecursor is 546 amino acids long (FIG. 88). Clone DNA35673-1201 hasbeen deposited with ATCC and is assigned ATCC deposit no. 209418.

Analysis of the amino acid sequence of the full-length PRO247polypeptide suggests that portions of it possess significant homology tothe densin molecule and KIAA0231, thereby indicating that PRO247 may bea novel leucine rich repeat protein.

Example 41 Isolation of cDNA Clones Encoding Human PRO302, PRO303,PRO304, PRO307 and PRO343

Consensus DNA sequences were assembled relative to other EST sequencesusing phrap as described in Example 1 above. These consensus sequencesare herein designated DNA35953, DNA35955, DNA35958, DNA37160 andDNA30895. Based on the DNA35953 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO302.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GTCCGCAAGGATGCCTACATGTTC-3′ (SEQ ID NO:264)forward PCR primer 2 5′-GCAGAGGTGTCTAAGGTTG-3′ (SEQ ID NO:265) reversePCR primer 5′-AGCTCTAGACCAATGCCAGCTTCC-3′ (SEQ ID NO:266)

Also, a synthetic oligonucleotide hybridization probe was constructedfrom the consensus DNA35953 sequence which had the following nucleotidesequence

hybridization probe 5′-GCCACCAACTCCTGCAAGAACTTCTCAGAACTGCCCCTGGTCATG-3′(SEQ ID NO:267)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO302 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue (LIB228).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO302 [herein designated as DNA40370-1217](SEQ ID NO:254) and the derived protein sequence for PRO302.

The entire nucleotide sequence of DNA40370-1217 is shown in FIG. 89 (SEQID NO:254). Clone DNA40370-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions34-36 and ending at the stop codon at nucleotide positions 1390-1392(FIG. 89). The predicted polypeptide precursor is 452 amino acids long(FIG. 90). Various unique aspects of the PRO302 protein are shown inFIG. 90. Clone DNA40370-1217 has been deposited with the ATCC on Nov.21, 1997 and is assigned ATCC deposit no. ATCC 209485.

Based on the DNA35955 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO303.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGGGAATTCACCCTATGACATTGCC-3′ (SEQ ID NO:268)reverse PCR primer 5′-GAATGCCCTGCAAGCATCAACTGG-3′ (SEQ ID NO:269)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35955 sequence which had the followingnucleotide sequence:

hybridization probe5′-GCACCTGTCACCTACACTAAACACATCCAGCCCATCTGTCTCCAGGCCTC-3′ (SEQ ID NO:270)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO303 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue (LIB25).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO303 [herein designated as DNA42551-1217](SEQ ID NO:256) and the derived protein sequence for PRO303.

The entire nucleotide sequence of DNA42551-1217 is shown in FIG. 91 (SEQID NO:256). Clone DNA42551-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions20-22 and ending at the stop codon at nucleotide positions 962-964 (FIG.91). The predicted polypeptide precursor is 314 amino acids long (FIG.92). Various unique aspects of the PRO303 protein are shown in FIG. 92.Clone DNA42551-1217 has been deposited on Nov. 21, 1997 with the ATCCand is assigned ATCC deposit no. ATCC 209483.

Based on the DNA35958 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO304.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GCGGAAGGGCAGAATGGGACTCCAAG-3′ (SEQ ID NO:271)forward PCR primer 2 5′-CAGCCCTGCCACATGTGC-3′ (SEQ ID NO:272) forwardPCR primer 3 5′-TACTGGGTGGTCAGCAAC-3′ (SEQ ID NO:273) reverse PCR primer5′-GGCGAAGAGCAGGGTGAGACCCCG-3′ (SEQ ID NO:274)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35958 sequence which had the followingnucleotide sequence

hybridization probe 5′-GCCCTCATCCTCTCTGGCAAATGCAGTTACAGCCCGGAGCCCGAC-3′(SEQ ID NO:275)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO304 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from 22 weekhuman fetal brain tissue (LIB153).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO304 [herein designated as DNA39520-1217](SEQ ID NO:258) and the derived protein sequence for PRO304.

The entire nucleotide sequence of DNA39520-1217 is shown in FIG. 93 (SEQID NO:258). Clone DNA39520-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions34-36 and ending at the stop codon at nucleotide positions 1702-1704(FIG. 93). The predicted polypeptide precursor is 556 amino acids long(FIG. 94). Various unique aspects of the PRO304 protein are shown inFIG. 94. Clone DNA39520-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209482.

Based on the DNA37160 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO307.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGGCAGGGATTCCAGGGCTCC-3′ (SEQ ID NO:276) forwardPCR primer 2 5′-GGCTATGACAGCAGGTTC-3′ (SEQ ID NO:277) forward PCR primer3 5′-TGACAATGACCGACCAGG-3′ (SEQ ID NO:278) reverse PCR primer5′-GCATCGCATTGCTGGTAGAGCAAG-3′ (SEQ ID NO:279)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA37160 sequence which had the followingnucleotide sequence

hybridization probe 5′-TTACAGTGCCCCCTGGAAACCCACTTGGCCTGCATACCGCCTCCC-3′(SEQ ID NO:280)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO307 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue (LIB229).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO307 [herein designated as DNA41225-1217](SEQ ID NO:260) and the derived protein sequence for PRO307.

The entire nucleotide sequence of DNA41225-1217 is shown in FIG. 95 (SEQID NO:260). Clone DNA41225-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions92-94 and ending at the stop codon at nucleotide positions 1241-1243(FIG. 95). The predicted polypeptide precursor is 383 amino acids long(FIG. 96). Various unique aspects of the PRO307 protein are shown inFIG. 96. Clone DNA41225-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209491.

Based on the DNA30895 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO343.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CGTCTCGAGCGCTCCATACAGTTCCCTTGCCCCA-3′ (SEQ IDNO:281) reverse PCR primer 5′-TGGAGGGGGAGCGGGATGCTTGTCTGGGCGACTCCGGGGGCC(SEQ ID NO:282) CCCTCATGTGCCAGGTGGA-3′

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30895 sequence which had the followingnucleotide sequence

hybridization probe5′-CCCTCAGACCCTGCAGAAGCTGAAGGTTCCTATCATCGACTCGGAAGTCTGCAGCCATCTG (SEQ IDNO:283) TACTGGCGGGGAGCAGGACAGGGACCCATCACTGAGGACATGCTGTGTGCCGGCTACT-3′

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO343 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue (LIB26).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO343 [herein designated as DNA43318-1217](SEQ ID NO:262) and the derived protein sequence for PRO343.

The entire nucleotide sequence of DNA43318-1217 is shown in FIG. 97 (SEQID NO:262). Clone DNA43318-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions53-55 and ending at the stop codon at nucleotide positions 1004-1006(FIG. 97). The predicted polypeptide precursor is 317 amino acids long(FIG. 98). Various unique aspects of the PRO343 protein are shown inFIG. 98. Clone DNA43318-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209481.

Example 42 Isolation of cDNA Clones Encoding Human PRO328

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35615. Based on the DNA35615 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO328.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-TCCTGCAGTTTCCTGATGC-3′ (SEQ ID NO:286) reverse PCRprimer 5′-CTCATATTGCACACCAGTAATTCG-3′ (SEQ ID NO:287)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35615 sequence which had the followingnucleotide sequence

hybridization probe 5′-ATGAGGAGAAACGTTTGATGGTGGAGCTGCACAACCTCTACCGGG-3′(SEQ ID NO:288)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO328 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO328 [herein designated as DNA40587-1231](SEQ ID NO:284) and the derived protein sequence for PRO328.

The entire nucleotide sequence of DNA40587-1231 is shown in FIG. 99 (SEQID NO:284). Clone DNA40587-1231 contains a single open reading framewith an apparent translational initiation site at nucleotide positions15-17 and ending at the stop codon at nucleotide positions 1404-1406(FIG. 99). The predicted polypeptide precursor is 463 amino acids long(FIG. 100). Clone DNA40587-1231 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209438.

Analysis of the amino acid sequence of the full-length PRO328polypeptide suggests that portions of it possess significant homology tothe human glioblastoma protein and to the cysteine rich secretoryprotein thereby indicating that PRO328 may be a novel glioblastomaprotein or cysteine rich secretory protein.

Example 43 Isolation of cDNA Clones Encoding Human PRO335, PRO331 orPRO326

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA36685. Based on the DNA36685 consensus sequence,and Incyte EST sequence no. 2228990, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO335, PRO331 or PRO326.

Forward and reverse PCR primers were synthesized for the determinationof PRO335:

forward PCR primer 5′-GGAACCGAATCTCAGCTA-3′ (SEQ ID NO:295) forward PCRprimer 5′-CCTAAACTGAACTGGACCA-3′ (SEQ ID NO:296) forward PCR primer5′-GGCTGGAGACACTGAACCT-3′ (SEQ ID NO:297) forward PCR primer5′-ACAGCTGCACAGCTCAGAACAGTG-3′ (SEQ ID NO:298) reverse PCR primer5′-CATTCCCAGTATAAAAATTTTC-3′ (SEQ ID NO:299) reverse PCR primer5′-GGGTCTTGGTGAATGAGG-3′ (SEQ ID NO:300) reverse PCR primer5′-GTGCCTCTCGGTTACCACCAATGG-3′ (SEQ ID NO:301)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO335 which had the followingnucleotide sequence

hybridization probe5′-GCGGCCACTGTTGGACCGAACTGTAACCAAGGGAGAAACAGCCGTCCTAC-3′ (SEQ ID NO:302)

Forward and reverse PCR primers were synthesized for the determinationof PRO331:

forward PCR primer 5′-GCCTTTGACAACCTTCAGTCACTAGTGG-3′ (SEQ ID NO:303)reverse PCR primer 5′-CCCCATGTGTCCATGACTGTTCCC-3′ (SEQ ID NO:304)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which had the followingnucleotide sequence

hybridization probe 5′-TACTGCCTCATGACCTCTTCACTCCCTTGCATCATCTTAGAGCGG-3′(SEQ ID NO:305)

Forward and reverse PCR primers were synthesized for the determinationof PRO326:

forward PCR primer 5′-ACTCCAAGGAAATCGGATCCGTTC-3′ (SEQ ID NO:306)reverse PCR primer 5′-TTAGCAGCTGAGGATGGGCACAAC-3′ (SEQ ID NO:307)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which had the followingnucleotide sequence

hybridization probe5′-GCCTTCACTGGTTTGGATGCATTGGAGCATCTAGACCTGAGTGACAACGC-3′ (SEQ ID NO:308)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO335, PRO331 or PRO326 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue (PRO335 and PRO326) and human fetal brain (PRO331).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO335, PRO331 or PRO326 [herein designatedas SEQ ID NOS:289, 291 and 293, respectively; see FIGS. 101, 103 and105, respectively], and the derived protein sequence for PRO335, PRO331or PRO326 (see FIGS. 102, 104 and 106, respectively; SEQ ID NOS:290, 292and 294, respectively).

The entire nucleotide sequences are shown in FIGS. 101, 103 and 105,deposited with the ATCC on Jun. 2, 1998, Nov. 7, 1997 and Nov. 21, 1997,respectively.

Analysis of the amino acid sequence of the full-length PRO335, PRO331 orPRO326 polypeptide suggests that portions of it possess significanthomology to the LIG-1 protein, thereby indicating that PRO335, PRO331and PRO326 may be a novel LIG-1-related protein.

Example 44 Isolation of cDNA clones Encoding Human PRO332

Based upon an ECD homology search performed as described in Example 1above, a consensus DNA sequence designated herein as DNA36688 wasassembled. Based on the DNA36688 consensus sequence, oligonucleotideswere synthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO332.

A pair of PCR primers (forward and reverse) were synthesized:

5′-GCATTGGCCGCGAGACTTTGCC-3′ (SEQ ID NO:311)5′-GCGGCCACGGTCCTTGGAAATG-3′ (SEQ ID NO:312)

A probe was also synthesized:

5′-TGGAGGAGCTCAACCTCAGCTACAACCGCATCACCAGCCCACAGG-3′ (SEQ ID NO:313)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO332 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a humanfetal liver library (LIB229).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for DNA40982-1235 and the derived proteinsequence for PRO332.

The entire nucleotide sequence of DNA40982-1235 is shown in FIG. 107(SEQ ID NO:309). Clone DNA40982-1235 contains a single open readingframe (with an apparent translational initiation site at nucleotidepositions 342-344, as indicated in FIG. 107). The predicted polypeptideprecursor is 642 amino acids long, and has a calculated molecular weightof 72,067 (pI: 6.60). Clone DNA40982-1235 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209433.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO332 shows about 30-40% amino acid sequenceidentity with a series of known proteoglycan sequences, including, forexample, fibromodulin and fibromodulin precursor sequences of variousspecies (FMOD_BOVIN, FMOD CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN,P_R36773), osteomodulin sequences (AB000114 1, AB007848_(—)1), decorinsequences (CFU83141_(—)1, OCU03394_(—)1, P_R42266, P_R42267, P_R42260,P_R89439) keratan sulfate proteoglycans (BTU48360_(—)1, AF022890_(—)1),corneal proteoglycan (AF022256_(—)1), and bone/cartilage proteoglycansand proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN).

Example 45 Isolation of cDNA clones Encoding Human PRO334

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. Based on the consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence for PRO334.

Forward and reverse PCR primers were synthesized for the determinationof PRO334:

forward PCR primer 5′-GATGGTTCCTGCTCAAGTGCCCTG-3′ (SEQ ID NO:316)reverse PCR primer 5′-TTGCACTTGTAGGACCCACGTACG-3′ (SEQ ID NO:317)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO334 which had the followingnucleotide sequence

hybridization probe5′-CTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCC-3′ (SEQ ID NO:318)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO334 gene using the probe oligonucleotideand one of the PCR primers.

Human fetal kidney cDNA libraries used to isolate the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO334 [herein designated as DNA41379-1236](SEQ ID NO:314) and the derived protein sequence for PRO334.

The entire nucleotide sequence of DNA41379-1236 (also referred to asUNQ295) is shown in FIG. 109 (SEQ ID NO:314). Clone DNA41379-1236contains a single open reading frame with an apparent translationalinitiation site at nucleotide positions 203-205 and ending at the stopcodon at nucleotide positions 1730-1732 (FIG. 109). The predictedpolypeptide precursor is 509 amino acids long (FIG. 110). CloneDNA41379-1236 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209488.

Analysis of the amino acid sequence of the full-length PRO334polypeptide suggests that portions of it possess significant homology tothe fibulin and fibrillin proteins, thereby indicating that PRO334 maybe a novel member of the EGF protein family.

Example 46 Isolation of cDNA Clones Encoding Human PRO346

A consensus DNA sequence was identified using phrap as described inExample 1 above. Specifically, this consensus sequence is hereindesignated DNA38240. Based on the DNA38240 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length PRO346 coding sequence.

RNA for construction of the cDNA libraries was isolated from human fetalliver. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagents(e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA wasprimed with oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof DNA44167-1243 is shown in FIG. 111 (SEQ ID NO:319). CloneDNA44167-1243 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 64-66 (FIG. I 11;SEQ ID NO:319). The predicted polypeptide precursor is 450 amino acidslong. Clone DNA44167-1243 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209434 (designation DNA44167-1243).

Based on a BLAST, BLAST-2 and FastA sequence alignment analysis (usingthe ALIGN computer program) of the full-length sequence, PRO346 showsamino acid sequence identity to carcinoembryonic antigen (28%).

The oligonucleotide sequences used in the above procedure were thefollowing:

OLI2691 (38240.f1) 5′-GATCCTGTCACAAAGCCAGTGGTGC-3′ (SEQ ID NO:321)OLI2693 (38240.r1) 5′-CACTGACAGGGTTCCTCACCCAGG-3′ (SEQ ID NO:322)OLI2692 (38240.p1) 5′-CTCCCTCTGGGCTGTGGAGTATGTGGGGAACATGACCCTGACATG-3′(SEQ ID NO:323)

Example 47 Isolation of cDNA Clones Encoding Human PRO268

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35698. Based on the DNA35698 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO268.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGAGGTGGGCAAGCGGCGAAATG-3′ (SEQ ID NO:326)forward PCR primer 2 5′-TATGTGGATCAGGACGTGCC-3′ (SEQ ID NO:327) forwardPCR primer 3 5′-TGCAGGGTTCAGTCTAGATTG-3′ (SEQ ID NO:328) reverse PCRprimer 5′-TTGAAGGACAAAGGCAATCTGCCAC-3′ (SEQ ID NO:329)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35698 sequence which had the followingnucleotide sequence

hybridization probe 5′-GGAGTCTTGCAGTTCCCCTGGCAGTCCTGGTGCTGTTGCTTTGGG-3′(SEQ ID NO:330)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO268 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO268 [herein designated as DNA39427-1179](SEQ ID NO:324) and the derived protein sequence for PRO268.

The entire nucleotide sequence of DNA39427-1179 is shown in FIG. 113(SEQ ID NO:324). Clone DNA39427-1179 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 13-15 and ending at the stop codon at nucleotide positions853-855 (FIG. 113). The predicted polypeptide precursor is 280 aminoacids long (FIG. 114). Clone DNA39427-1179 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209395.

Analysis of the amino acid sequence of the full-length PRO268polypeptide suggests that it possess significant homology to proteindisulfide isomerase, thereby indicating that PRO268 may be a novelprotein disulfide isomerase.

Example 48 Isolation of cDNA Clones Encoding Human PRO330

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35730. Based on the DNA35730 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO330.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-CCAGGCACAATTTCCAGA-3′ (SEQ ID NO:333) forwardPCR primer 2 5′-GGACCCTTCTGTGTGCCAG-3′ (SEQ ID NO:334) reverse PCRprimer 1 5′-GGTCTCAAGAACTCCTGTC-3′ (SEQ ID NO:335) reverse PCR primer 25′-ACACTCAGCATTGCCTGGTACTTG-3′ (SEQ ID NO:336)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

hybridization probe 5′-GGGCACATGACTGACCTGATTTATGCAGAGAAAGAGCTGGTGCAG-3′(SEQ ID NO:337)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO330 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO330 [herein designated as DNA40603-1232](SEQ ID NO:331) and the derived protein sequence for PRO330.

The entire nucleotide sequence of DNA40603-1232 is shown in FIG. 115(SEQ ID NO:331). Clone DNA40603-1232 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 167-169 and ending at the stop codon at nucleotide positions1766-1768 (FIG. 115). The predicted polypeptide precursor is 533 aminoacids long (FIG. 116). Clone DNA40603-1232 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209486 on Nov. 21, 1997.

Analysis of the amino acid sequence of the full-length PRO330polypeptide suggests that portions of it possess significant homology tothe mouse prolyl 4-hydroxylase alpha subunit protein, thereby indicatingthat PRO330 may be a novel prolyl 4-hydroxylase alpha subunitpolypeptide.

Example 49 Isolation of cDNA Clones Encoding Human PRO310

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA40553. Based on the DNA40553 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO310.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TCCCCAAGCCGTTCTAGACGCGG-3′ (SEQ ID NO:342)forward PCR primer 2 5′-CTGGTTCTTCCTTGCACG-3′ (SEQ ID NO:343) reversePCR primer 5′-GCCCAAATGCCCTAAGGCGGTATACCCC-3′ (SEQ ID NO:344)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

hybridization probe5′-GGGTGTGATGCTTGGAAGCATTTTCTGTGCTTTGATCACTATGCTAGGAC-3′ (SEQ ID NO:345)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO310 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO310 [herein designated as DNA43046-1225(SEQ ID NO:340) and the derived protein sequence for PRO310 (SEQ IDNO:341).

The entire nucleotide sequence of DNA43046-1225 is shown in FIG. 119(SEQ ID NO:340). Clone DNA43046-1225 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 81-83 and ending at the stop codon at nucleotide positions1035-1037 (FIG. 119). The predicted polypeptide precursor is 318 aminoacids long (FIG. 120) and has a calculated molecular weight ofapproximately 36,382 daltons. Clone DNA43046-1225 has been depositedwith ATCC and is assigned ATCC deposit no. ATCC 209484.

Analysis of the amino acid sequence of the full-length PRO310polypeptide suggests that portions of it possess homology to C. elegansproteins and to fringe, thereby indicating that PRO310 may be involvedin development.

Example 50 Isolation of cDNA clones Encoding Human PRO339

An expressed sequence tag (EST) DNA database (LIFESEQ™, IncytePharmaceuticals, Palo Alto, Calif.) was searched and ESTs wereidentified. An assembly of Incyte clones and a consensus sequence wasformed using phrap as described in Example 1 above.

Forward and reverse PCR primers were synthesized based upon theassembly-created consensus sequence:

forward PCR primer 1 5′-GGGATGCAGGTGGTGTCTCATGGGG-3′ (SEQ ID NO:346)forward PCR primer 2 5′-CCCTCATGTACCGGCTCC-3′ (SEQ ID NO:347) forwardPCR primer 3 5′-GTGTGACACAGCGTGGGC-3′ (SEQ ID NO:43) forward PCR primer4 5′-GACCGGCAGGCTTCTGCG-3′ (SEQ ID NO:44) reverse PCR primer 15′-CAGCAGCTTCAGCCACCAGGAGTGG-3′ (SEQ ID NO:45) reverse PCR primer 25′-CTGAGCCGTGGGCTGCAGTCTCGC-3′ (SEQ ID NO:46)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

hybridization probe 5′-CCGACTACGACTGGTTCTTCATCATGCAGGATGACACATATGTGC-3′(SEQ ID NO:47)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO339 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof DNA43466-1225 is shown in FIG. 117 (SEQ ID NO:338). CloneDNA43466-1225 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 333-335 and endingat the stop codon found at nucleotide positions 2649-2651 (FIG. 117; SEQID NO:338). The predicted polypeptide precursor is 772 amino acids longand has a calculated molecular weight of approximately 86,226 daltons.Clone DNA43466-1225 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209490.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGNcomputer program) of the full-length sequence, PRO339 has homology to C.elegans proteins and collagen-like polymer sequences as well as tofringe, thereby indicating that PRO339 may be involved in development ortissue growth.

Example 51 Isolation of cDNA Clones Encoding Human PRO244

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. Based on this consensussequence, oligonucleotides were synthesized to identify by PCR a cDNAlibrary that contained the sequence of interest and for use as probes toisolate a clone of the full-length coding sequence for PRO244.

A pair of PCR primers (forward and reverse) were synthesized:

5′-TTCAGCTTCTGGGATGTAGGG-3′ (30923.f1) (SEQ ID NO:378)5′-TATTCCTACCATTTCACAAATCCG-3′ (30923.r1) (SEQ ID NO:379)

A probe was also synthesized:

5′-GGAGGACTGTGCCACCATGAGAGACTCTTCAAACCCAAGGCAAAATTGG-3′ (30923.p1) (SEQID NO:380)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO244 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a humanfetal kidney library. DNA sequencing of the clones isolated as describedabove gave the full-length DNA sequence and the derived protein sequencefor PRO244.

The entire nucleotide sequence of PRO244 is shown in FIG. 121 (SEQ IDNO:376). Clone DNA35668-1171 contains a single open reading frame withan apparent translational initiation site at nucleotide positions106-108 (FIG. 121). The predicted polypeptide precursor is 219 aminoacids long. Clone DNA35668-1171 has been deposited with ATCC (designatedas DNA35663-1171) and is assigned ATCC deposit no. ATCC209371. Theprotein has a cytoplasmic domain (aa 1-20), a transmembrane domain (aa21-46), and an extracellular domain (aa 47-219), with a C-lectin domainat aa 55-206.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO244 shows notable amino acid sequence identityto hepatic lectin gallus gallus (43%), HIC hp120-binding C-type lectin(42%), macrophage lectin 2 (HUMHML2-1, 41%), and sequence PR32188 (44%).

Example 52 Use of PRO Polypeptide-Encoding Nucleic Acid as HybridizationProbes

The following method describes use of a nucleotide sequence encoding aPRO polypeptide as a hybridization probe.

DNA comprising the coding sequence of of a PRO polypeptide of interestas disclosed herein may be employed as a probe or used as a basis fromwhich to prepare probes to screen for homologous DNAs (such as thoseencoding naturally-occurring variants of the PRO polypeptide) in humantissue cDNA libraries or human tissue genomic libraries.

Hybridization and washing of filters containing either library DNAs isperformed under the following high stringency conditions. Hybridizationof radiolabeled PRO polypeptide-encoding nucleic acid-derived probe tothe filters is performed in a solution of 50% formamide, 5× SSC, 0.1%SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2×Denhardt's solution, and 10% dextran sulfate at 42° C. for 20 hours.Washing of the filters is performed in an aqueous solution of 01× SSCand 0.1% SDS at 42° C.

DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO polypeptide can then be identified usingstandard techniques known in the art.

Example 53 Expression of PRO Polypeptides in E. coli

This example illustrates preparation of an unglycosylated form of adesired PRO polypeptide by recombinant expression in E. coli.

The DNA sequence encoding the desired PRO polypeptide is initiallyamplified using selected PCR primers. The primers should containrestriction enzyme sites which correspond to the restriction enzymesites on the selected expression vector. A variety of expression vectorsmay be employed. An example of a suitable vector is pBR322 (derived fromE. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes forampicillin and tetracycline resistance. The vector is digested withrestriction enzyme and dephosphorylated. The PCR amplified sequences arethen ligated into the vector. The vector will preferably includesequences which encode for an antibiotic resistance gene, a trppromoter, a polyhis leader (including the first six STII codons, polyhissequence, and enterokinase cleavage site), the specific PRO polypeptidecoding region, lambda transcriptional terminator, and an argU gene.

The ligation mixture is then used to transform a selected E. coli strainusing the methods described in Sambrook et al., supra. Transformants areidentified by their ability to grow on LB plates and antibioticresistant colonies are then selected. Plasmid DNA can be isolated andconfirmed by restriction analysis and DNA sequencing.

Selected clones can be grown overnight in liquid culture medium such asLB broth supplemented with antibiotics. The overnight culture maysubsequently be used to inoculate a larger scale culture. The cells arethen grown to a desired optical density, during which the expressionpromoter is turned on.

After culturing the cells for several more hours, the cells can beharvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the solubilized PRO polypeptide can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

PRO187, PRO317, PRO301, PRO224 and PRO238 were successfully expressed inE. coli in a poly-His tagged form, using the following procedure. TheDNA encoding PRO187, PRO317, PRO301, PRO224 or PRO238 was initiallyamplified using selected PCR primers. The primers contained restrictionenzyme sites which correspond to the restriction enzyme sites on theselected expression vector, and other useful sequences providing forefficient and reliable translation initiation, rapid purification on ametal chelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences were then ligated into anexpression vector, which was used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) Ion galE rpoHts(htpRts) clpP(lacIq).Transformants were first grown in LB containing 50 mg/ml carbenicillinat 30° C. with shaking until an O.D.600 of 3-5 was reached. Cultureswere then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate-2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples were removedto verify expression by SDS-PAGE analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets were frozen untilpurification and refolding.

E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) wasresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02 M, respectively, and the solutionwas stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution wascentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant was diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. Depending the clarified extract was loaded onto a 5mil Qiagen Ni-NTA metal chelate column equilibrated in the metal chelatecolumn buffer. The column was washed with additional buffer containing50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein waseluted with buffer containing 250 mM imidazole. Fractions containing thedesired protein were pooled and stored at 4° C. Protein concentrationwas estimated by its absorbance at 280 nm using the calculatedextinction coefficient based on its amino acid sequence.

The proteins were refolded by diluting sample slowly into freshlyprepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl,2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refoldingvolumes were chosen so that the final protein concentration was between50 to 100 micrograms/ml. The refolding solution was stirred gently at 4°C. for 12-36 hours. The refolding reaction was quenched by the additionof TFA to a final concentration of 0.4% (pH of approximately 3). Beforefurther purification of the protein, the solution was filtered through a0.22 micron filter and acetonitrile was added to 2-10% finalconcentration. The refolded protein was chromatographed on a Poros R1/Hreversed phase column using a mobile buffer of 0.1% TFA with elutionwith a gradient of acetonitrile from 10 to 80%. Aliquots of fractionswith A280 absorbance were analyzed on SDS polyacrylamide gels andfractions containing homogeneous refolded protein were pooled.Generally, the properly refolded species of most proteins are eluted atthe lowest concentrations of acetonitrile since those species are themost compact with their hydrophobic interiors shielded from interactionwith the reversed phase resin. Aggregated species are usually eluted athigher acetonitrile concentrations. In addition to resolving misfoldedforms of proteins from the desired form, the reversed phase step alsoremoves endotoxin from the samples.

Fractions containing the desired folded PRO187, PRO317, PRO301, PRO224and PRO238 proteins, respectively, were pooled and the acetonitrileremoved using a gentle stream of nitrogen directed at the solution.Proteins were formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodiumchloride and 4% mannitol by dialysis or by gel filtration using G25Superfine (Pharmacia) resins equilibrated in the formulation buffer andsterile filtered.

Example 54 Expression of PRO Polypeptides in Mammalian Cells

This example illustrates preparation of a glycosylated form of a desiredPRO polypeptide by recombinant expression in mammalian cells.

The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employedas the expression vector. Optionally, the PRO polypeptide-encoding DNAis ligated into pRK5 with selected restriction enzymes to allowinsertion of the PRO polypeptide DNA using ligation methods such asdescribed in Sambrook et al., supra. The resulting vector is calledpRK5-PRO polypeptide.

In one embodiment, the selected host cells may be 293 cells. Human 293cells (ATCC CCL 1573) are grown to confluence in tissue culture platesin medium such as DMEM supplemented with fetal calf serum andoptionally, nutrient components and/or antibiotics. About 10 μg pRK5-PROpolypeptide DNA is mixed with about 1 μg DNA encoding the VA RNA gene[Thimmappaya et al., Cell 31:543 (1982)] and dissolved in 500 μl of I mMTris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added,dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄,and a precipitate is allowed to form for 10 minutes at 25° C. Theprecipitate is suspended and added to the 293 cells and allowed tosettle for about four hours at 37° C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293cells are then washed with serum free medium, fresh medium is added andthe cells are incubated for about 5 days.

Approximately 24 hours after the transfections, the culture medium isremoved and replaced with culture medium (alone) or culture mediumcontaining 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine. Aftera 12 hour incubation, the conditioned medium is collected, concentratedon a spin filter, and loaded onto a 15% SDS gel. The processed gel maybe dried and exposed to film for a selected period of time to reveal thepresence of PRO polypeptide. The cultures containing transfected cellsmay undergo further incubation (in serum free medium) and the medium istested in selected bioassays.

In an alternative technique, PRO polypeptide may be introduced into 293cells transiently using the dextran sulfate method described bySomparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells aregrown to maximal density in a spinner flask and 700 μg pRK5-PROpolypeptide DNA is added. The cells are first concentrated from thespinner flask by centrifugation and washed with PBS. The DNA-dextranprecipitate is incubated on the cell pellet for four hours. The cellsare treated with 20% glycerol for 90 seconds, washed with tissue culturemedium, and re-introduced into the spinner flask containing tissueculture medium, 5 μg/ml bovine insulin and 0.1 μg/ml bovine transferrin.After about four days, the conditioned media is centrifuged and filteredto remove cells and debris. The sample containing expressed PROpolypeptide can then be concentrated and purified by any selectedmethod, such as dialysis and/or column chromatography.

In another embodiment, PRO polypeptides can be expressed in CHO cells.The pRK5-PRO polypeptide can be transfected into CHO cells using knownreagents such as CaPO₄ or DEAE-dextran. As described above, the cellcultures can be incubated, and the medium replaced with culture medium(alone) or medium containing a radiolabel such as ³⁵S-methionine. Afterdetermining the presence of PRO polypeptide, the culture medium may bereplaced with serum free medium. Preferably, the cultures are incubatedfor about 6 days, and then the conditioned medium is harvested. Themedium containing the expressed PRO polypeptide can then be concentratedand purified by any selected method.

Epitope-tagged PRO polypeptide may also be expressed in host CHO cells.The PRO polypeptide may be subcloned out of the pRK5 vector. Thesubclone insert can undergo PCR to fuse in frame with a selected epitopetag such as a poly-his tag into a Baculovirus expression vector. Thepoly-his tagged PRO polypeptide insert can then be subcloned into a SV40driven vector containing a selection marker such as DHFR for selectionof stable clones. Finally, the CHO cells can be transfected (asdescribed above) with the SV40 driven vector. Labeling may be performed,as described above, to verify expression. The culture medium containingthe expressed poly-His tagged PRO polypeptide can then be concentratedand purified by any selected method, such as by Ni²⁺-chelate affinitychromatography.

PRO211, PRO217, PRO230, PRO219, PRO245, PRO221, PRO258, PRO301, PRO224,PRO222,

PRO234, PRO229, PRO223, PRO328 and PRO332 were successfully expressed inCHO cells by both a transient and a stable expression procedure. Inaddition, PRO232, PRO265, PRO246, PRO228, PRO227, PRO220, PRO266,PRO269, PRO287, PRO214, PRO231, PRO233, PRO238, PRO244, PRO235, PRO236,PRO262, PRO239, PRO257, PRO260, PRO263, PRO270, PRO271, PRO272, PRO294,PRO295, PRO293, PRO247, PRO303 and PRO268 were successfully transientlyexpressed in CHO cells.

Stable expression in CHO cells was performed using the followingprocedure. The proteins were expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins were fused to anIgG1 constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

Following PCR amplification, the respective DNAs were subcloned in a CHOexpression vector using standard techniques as described in Ausubel etal., Current Protocols of Molecular Biology, Unit 3.16, John Wiley andSons (1997). CHO expression vectors are constructed to have compatiblerestriction sites 5′ and 3′ of the DNA of interest to allow theconvenient shuttling of cDNA's. The vector used expression in CHO cellsis as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe cDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

Twelve micrograms of the desired plasmid DNA were introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Quiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells were grown and described in Lucas etal., supra. Approximately 3×10⁻⁷ cells are frozen in an ampule forfurther growth and production as described below.

The ampules containing the plasmid DNA were thawed by placement intowater bath and mixed by vortexing. The contents were pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant was aspirated and the cells wereresuspended in 10 mL of selective media (0.2,μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells were then aliquotedinto a 100 mL spinner containing 90 mL of selective media. After 1-2days, the cells were transferred into a 250 mL spinner filled with 150mL selective growth medium and incubated at 37° C. After another 2-3days, a 250 m 500 mL and 2000 mL spinners were seeded with 3×10⁵cells/mL. The cell media was exchanged with fresh media bycentrifugation and resuspension in production medium. Although anysuitable CHO media may be employed, a production medium described inU.S. Pat. No. 5,122,469, issued Jun. 16, 1992 was actually used. 3Lproduction spinner is seeded at 1.2×10⁶ cells/mL. On day 0, the cellnumber pH were determined. On day 1, the spinner was sampled andsparging with filtered air was commenced. On day 2, the spinner wassampled, the temperature shifted to 33° C., and 30 mL of 500 g/L glucoseand 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, DowCorning 365 Medical Grade Emulsion). Throughout the production, pH wasadjusted as necessary to keep at around 7.2. After 10 days, or untilviability dropped below 70%, the cell culture was harvested bycentrifugtion and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

For the poly-His tagged constructs, the proteins were purified using aNi-NTA column (Qiagen). Before purification, imidazole was added to theconditioned media to a concentration of 5 mM. The conditioned media waspumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4,buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5ml/min. at 4° C. After loading, the column was washed with additionalequilibration buffer and the protein eluted with equilibration buffercontaining 0.25 M imidazole. The highly purified protein wassubsequently desalted into a storage buffer containing 10 mM Hepes, 0.14M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia)column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of were purified from theconditioned media as follows. The conditioned medium was pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column was washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein was immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein was subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity was assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

PRO211, PRO217, PRO230, PRO232, PRO187, PRO265, PRO219, PRO246, PRO228,PRO533, PRO245, PRO221, PRO227, PRO220, PRO258, PRO266, PRO269, PRO287,PRO214, PRO317, PRO301, PRO224, PRO222, PRO234, PRO231, PRO229, PRO233,PRO238, PRO223, PRO235, PRO236, PRO262, PRO239, PRO257, PRO260, PRO263,PRO270, PRO271, PRO272, PRO294, PRO295, PRO293, PRO247, PRO304, PRO302,PRO307, PRO303, PRO343, PRO328, PRO326, PRO331, PRO332, PRO334, PRO346,PRO268, PRO330, PRO310 and PRO339 were also successfully transientlyexpressed in COS cells.

Example 55 Expression of PRO Polypeptides in Yeast

The following method describes recombinant expression of a desired PROpolypeptide in yeast.

First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO polypeptides from the ADH2/GAPDHpromoter. DNA encoding a desired PRO polypeptide, a selected signalpeptide and the promoter is inserted into suitable restriction enzymesites in the selected plasmid to direct intracellular expression of thePRO polypeptide. For secretion, DNA encoding the PRO polypeptide can becloned into the selected plasmid, together with DNA encoding theADH2/GAPDH promoter, the yeast alpha-factor secretory signal/leadersequence, and linker sequences (if needed) for expression of the PROpolypeptide.

Yeast cells, such as yeast strain AB110, can then be transformed withthe expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

Recombinant PRO polypeptide can subsequently be isolated and purified byremoving the yeast cells from the fermentation medium by centrifugationand then concentrating the medium using selected cartridge filters. Theconcentrate containing the PRO polypeptide may further be purified usingselected column chromatography resins.

Example 56 Expression of PRO Polypeptides in Baculovirus-Infected InsectCells

The following method describes recombinant expression of PROpolypeptides in Baculovirus-infected insect cells.

The desired PRO polypeptide is fused upstream of an epitope tagcontained with a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fc regions of IgG).A variety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pVL1393 (Novagen). Briefly, thePRO polypeptide or the desired portion of the PRO polypeptide (such asthe sequence encoding the extracellular domain of a transmembraneprotein) is amplified by PCR with primers complementary to the 5′ and 3′regions. The 5′ primer may incorporate flanking (selected) restrictionenzyme sites. The product is then digested with those selectedrestriction enzymes and subcloned into the expression vector.

Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold® virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28° C., thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression is performed as described byO'Reilley et al., Baculovirus expression vectors: A laboratory Manual,Oxford: Oxford University Press (1994).

Expressed poly-his tagged PRO polypeptide can then be purified, forexample, by Ni²⁺-chelate affinity chromatography as follows. Extractsare prepared from recombinant virus-infected Sf9 cells as described byRupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells arewashed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mMMgCl₂; 0.1 mM EDTA; 10% Glycerol; 0.1% NP40; 0.4 M KCl), and sonicatedtwice for 20 seconds on ice. The sonicates are cleared bycentrifugation, and the supernatant is diluted 50-fold in loading buffer(50 mM phosphate, 300 mM NaCl, 10% Glycerol, pH 7.8) and filteredthrough a 0.45 μm filter. A Ni²⁺-NTA agarose column (commerciallyavailable from Qiagen) is prepared with a bed volume of 5 mL, washedwith 25 mL of water and equilibrated with 25 mL of loading buffer. Thefiltered cell extract is loaded onto the column at 0.5 mL per minute.The column is washed to baseline A₂₈₀ with loading buffer, at whichpoint fraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% Glycerol, pH6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀baseline again, the column is developed with a 0 to 500 mM Imidazolegradient in the secondary wash buffer. One mL fractions are collectedand analyzed by SDS-PAGE and silver staining or western blot withNi²⁺-NTA-conjugated to alkaline phosphatase (Qiagen). Fractionscontaining the eluted His₁₀-tagged PRO polypeptide are pooled anddialyzed against loading buffer.

Alternatively, purification of the IgG tagged (or Fc tagged) PROpolypeptide can be performed using known chromatography techniques,including for instance, Protein A or protein G column chromatography.

PRO211, PRO217, PRO230, PRO187, PRO265, PRO246, PRO228, PRO533, PRO245,PRO221, PRO220, PRO258, PRO266, PRO269, PRO287, PRO214, PRO301, PRO224,PRO222, PRO234, PRO231, PRO229, PRO235, PRO239, PRO257, PRO272, PRO294,PRO295, PRO328, PRO326, PRO331, PRO334, PRO346 and PRO310 weresuccessfully expressed in baculovirus infected Sf9 or high5 insectcells. While the expression was actually performed in a 0.5-2 L scale,it can be readily scaled up for larger (e.g. 8 L) preparations. Theproteins were expressed as an IgG construct (immunoadhesin), in whichthe protein extracellular region was fused to an IgG1 constant regionsequence containing the hinge, CH2 and CH3 domains and/or in poly-Histagged forms.

Following PCR amplification, the respective coding sequences weresubcloned into a baculovirus expression vector (pb.PH.IgG for IgGfusions and pb.PH.His.c for poly-His tagged proteins), and the vectorand Baculogold® baculovirus DNA (Pharmingen) were co-transfected into105 Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711), usingLipofectin (Gibco BRL). pb.PH.IgG and pb.PH.His are modifications of thecommercially available baculovirus expression vector pVL1393(Pharmingen), with modified polylinker regions to include the His or Fctag sequences. The cells were grown in Hink's TNM-FH medium supplementedwith 10% FBS (Hyclone). Cells were incubated for 5 days at 28° C. Thesupernatant was harvested and subsequently used for the first viralamplification by infecting Sf9 cells in Hink's TNM-FH mediumsupplemented with 10% FBS at an approximate multiplicity of infection(MOI) of 10. Cells were incubated for 3 days at 28° C. The supernatantwas harvested and the expression of the constructs in the baculovirusexpression vector was determined by batch binding of 1 ml of supernatantto 25 mL of Ni-NTA beads (QIAGEN) for histidine tagged proteins orProtein-A Sepharose CL-4B beads (Pharmacia) for IgG tagged proteinsfollowed by SDS-PAGE analysis comparing to a known concentration ofprotein standard by Coomassie blue staining.

The first viral amplification supernatant was used to infect a spinnerculture (500 ml) of Sf9 cells grown in ESF-921 medium (ExpressionSystems LLC) at an approximate MOI of 0.1. Cells were incubated for 3days at 28° C. The supernatant was harvested and filtered. Batch bindingand SDS-PAGE analysis was repeated, as necessary, until expression ofthe spinner culture was confirmed.

The conditioned medium from the transfected cells (0.5 to 3 L) washarvested by centrifugation to remove the cells and filtered through0.22 micron filters. For the poly-His tagged constructs, the proteinconstruct were purified using a Ni-NTA column (Qiagen). Beforepurification, imidazole was added to the conditioned media to aconcentration of 5 mM. The conditioned media were pumped onto a 6 mlNi-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. Afterloading, the column was washed with additional equilibration buffer andthe protein eluted with equilibration buffer containing 0.25 Mimidazole. The highly purified protein was subsequently desalted into astorage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of proteins were purified fromthe conditioned media as follows. The conditioned media were pumped ontoa 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mMNa phosphate buffer, pH 6.8. After loading, the column was washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein was immediately neutralized bycollecting 1 ml fractions into tubes containing 275 mL of 1 M Trisbuffer, pH 9. The highly purified protein was subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity of the proteins was verified by SDS polyacrylamide gel (PEG)electrophoresis and N-terminal amino acid sequencing by Edmandegradation.

Example 57 Preparation of Antibodies that Bind to PRO Polypeptides

This example illustrates preparation of monoclonal antibodies which canspecifically bind to a PRO polypeptide.

Techniques for producing the monoclonal antibodies are known in the artand are described, for instance, in Goding, supra. Immunogens that maybe employed include purified PRO polypeptide, fusion proteins containingthe PRO polypeptide, and cells expressing recombinant PRO polypeptide onthe cell surface. Selection of the immunogen can be made by the skilledartisan without undue experimentation.

Mice, such as Balb/c, are immunized with the PRO polypeptide immunogenemulsified in complete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-PRO polypeptide antibodies.

After a suitable antibody titer has been detected, the animals“positive” for antibodies can be injected with a final intravenousinjection of PRO polypeptide. Three to four days later, the mice aresacrificed and the spleen cells are harvested. The spleen cells are thenfused (using 35% polyethylene glycol) to a selected murine myeloma cellline such as P3X63AgU.1, available from ATCC, No. CRL 1597. The fusionsgenerate hybridoma cells which can then be plated in 96 well tissueculture plates containing HAT (hypoxanthine, aminopterin, and thymidine)medium to inhibit proliferation of non-fused cells, myeloma hybrids, andspleen cell hybrids.

The hybridoma cells will be screened in an ELISA for reactivity againstthe PRO polypeptide. Determination of “positive” hybridoma cellssecreting the desired monoclonal antibodies against the PRO polypeptideis within the skill in the art.

The positive hybridoma cells can be injected intraperitoneally intosyngeneic Balb/c mice to produce ascites containing the anti-PROpolypeptide monoclonal antibodies. Alternatively, the hybridoma cellscan be grown in tissue culture flasks or roller bottles. Purification ofthe monoclonal antibodies produced in the ascites can be accomplishedusing ammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can be employed.

Example 58 Chimeric PRO Polypeptides

PRO polypeptides may be expressed as chimeric proteins with one or moreadditional polypeptide domains added to facilitate protein purification.Such purification facilitating domains include, but are not limited to,metal chelating peptides such as histidine-tryptophan modules that allowpurification on immobilized metals, protein A domains that allowpurification on immobilized immunoglobulin, and the domain utilized inthe FLAGS™ extension/affinity purification system (Immunex Corp.,Seattle Wash.). The inclusion of a cleavable linker sequence such asFactor XA or enterokinase (Invitrogen, San Diego Calif.) between thepurification domain and the PRO polypeptide sequence may be useful tofacilitate expression of DNA encoding the PRO polypeptide.

Example 59 Purification of PRO Polypeptides Using Specific Antibodies

Native or recombinant PRO polypeptides may be purified by a variety ofstandard techniques in the art of protein purification. For example,pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide ispurified by immunoaffinity chromatography using antibodies specific forthe PRO polypeptide of interest. In general, an immunoaffinity column isconstructed by covalently coupling the anti-PRO polypeptide antibody toan activated chromatographic resin.

Polyclonal immunoglobulins are prepared from immune sera either byprecipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

Such an immunoaffinity column is utilized in the purification of PROpolypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble PRO polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

A soluble PRO polypeptide-containing preparation is passed over theimmunoaffinity column, and the column is washed under conditions thatallow the preferential absorbance of PRO polypeptide (e.g., high ionicstrength buffers in the presence of detergent). Then, the column iseluted under conditions that disrupt antibody/PRO polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and PROpolypeptide is collected.

Example 60 Drug Screening

This invention is particularly useful for screening compounds by usingPRO polypeptides or binding fragment thereof in any of a variety of drugscreening techniques. The PRO polypeptide or fragment employed in such atest may either be free in solution, affixed to a solid support, borneon a cell surface, or located intracellularly. One method of drugscreening utilizes eukaryotic or prokaryotic host cells which are stablytransformed with recombinant nucleic acids expressing the PROpolypeptide or fragment. Drugs are screened against such transformedcells in competitive binding assays. Such cells, either in viable orfixed form, can be used for standard binding assays. One may measure,for example, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examine thediminution in complex formation between the PRO polypeptide and itstarget cell or target receptors caused by the agent being tested.

Thus, the present invention provides methods of screening for drugs orany other agents which can affect a PRO polypeptide-associated diseaseor disorder. These methods comprise contacting such an agent with an PROpolypeptide or fragment thereof and assaying (I) for the presence of acomplex between the agent and the PRO polypeptide or fragment, or (ii)for the presence of a complex between the PRO polypeptide or fragmentand the cell, by methods well known in the art. In such competitivebinding assays, the PRO polypeptide or fragment is typically labeled.After suitable incubation, free PRO polypeptide or fragment is separatedfrom that present in bound form, and the amount of free or uncomplexedlabel is a measure of the ability of the particular agent to bind to PROpolypeptide or to interfere with the PRO polypeptide/cell complex.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to a polypeptide and isdescribed in detail in WO 84/03564, published on Sep. 13, 1984. Brieflystated, large numbers of different small peptide test compounds aresynthesized on a solid substrate, such as plastic pins or some othersurface. As applied to a PRO polypeptide, the peptide test compounds arereacted with PRO polypeptide and washed. Bound PRO polypeptide isdetected by methods well known in the art. Purified PRO polypeptide canalso be coated directly onto plates for use in the aforementioned drugscreening techniques. In addition, non-neutralizing antibodies can beused to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding PROpolypeptide specifically compete with a test compound for binding to PROpolypeptide or fragments thereof. In this manner, the antibodies can beused to detect the presence of any peptide which shares one or moreantigenic determinants with PRO polypeptide.

Example 61 Rational Drug Design

The goal of rational drug design is to produce structural analogs ofbiologically active polypeptide of interest (i.e., a PRO polypeptide) orof small molecules with which they interact, e.g., agonists,antagonists, or inhibitors. Any of these examples can be used to fashiondrugs which are more active or stable forms of the PRO polypeptide orwhich enhance or interfere with the function of the PRO polypeptide invivo (cf., Hodgson, Bio/Technology, 9:19-21 (1991)).

In one approach, the three-dimensional structure of the PRO polypeptide,or of an PRO polypeptide-inhibitor complex, is determined by x-raycrystallography, by computer modeling or, most typically, by acombination of the two approaches. Both the shape and charges of the PROpolypeptide must be ascertained to elucidate the structure and todetermine active site(s) of the molecule. Less often, useful informationregarding the structure of the PRO polypeptide may be gained by modelingbased on the structure of homologous proteins. In both cases, relevantstructural information is used to design analogous PRO polypeptide-likemolecules or to identify efficient inhibitors. Useful examples ofrational drug design may include molecules which have improved activityor stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of nativepeptides as shown by Athauda et al., J. Biochem., 113:742-746 (1993).

It is also possible to isolate a target-specific antibody, selected byfunctional assay, as described above, and then to solve its crystalstructure. This approach, in principle, yields a pharmacore upon whichsubsequent drug design can be based. It is possible to bypass proteincrystallography altogether by generating anti-idiotypic antibodies(anti-ids) to a functional, pharmacologically active antibody. As amirror image of a mirror image, the binding site of the anti-ids wouldbe expected to be an analog of the original receptor. The anti-id couldthen be used to identify and isolate peptides from banks of chemicallyor biologically produced peptides. The isolated peptides would then actas the pharmacore.

By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analytical studies asX-ray crystallography. In addition, knowledge of the PRO polypeptideamino acid sequence provided herein will provide guidance to thoseemploying computer modeling techniques in place of or in addition tox-ray crystallography.

Example 62 Diagnostic Test Using PRO317 Polypeptide-Specific Antibodies

Particular anti-PRO317 polypeptide antibodies are useful for thediagnosis of prepathologic conditions, and chronic or acute diseasessuch as gynecological diseases or ischemic diseases which arecharacterized by differences in the amount or distribution of PRO317.PRO317 has been found to be expressed in human kidney and is thus likelyto be associated with abnormalities or pathologies which affect thisorgan. Further, since it is so closely related to EBAF-1, it is likelyto affect the endometrium and other genital tissues. Further, due tolibrary sources of certain ESTs, it appears that PRO317 may be involvedas well in forming blood vessels and hence to be a modulator ofangiogenesis.

Diagnostic tests for PRO317 include methods utilizing the antibody and alabel to detect PRO317 in human body fluids, tissues, or extracts ofsuch tissues. The polypeptide and antibodies of the present inventionmay be used with or without modification. Frequently, the polypeptideand antibodies will be labeled by joining them, either covalently ornoncovalently, with a substance which provides for a detectable signal.A wide variety of labels and conjugation techniques are known and havebeen reported extensively in both the scientific and patent literature.Suitable labels include radionuclides, enzymes, substrates, cofactors,inhibitors, fluorescent agents, chemiluminescent agents, magneticparticles, and the like. Patents teaching the use of such labels includeU.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437;4,275,149; and 4,366,241. Also, recombinant immunoglobulins may beproduced as shown in U.S. Pat. No. 4,816,567.

A variety of protocols for measuring soluble or membrane-bound PRO317,using either polyclonal or monoclonal antibodies specific for thatPRO317, are known in the art. Examples include enzyme-linkedimmunosorbent assay (ELISA), radioimmunoassay (RIA), radioreceptor assay(RRA), and fluorescent activated cell sorting (FACS). A two-sitemonoclonal-based immunoassay utilizing monoclonal antibodies reactive totwo non-interfering epitopes on PRO317 is preferred, but a competitivebinding assay may be employed. These assays are described, among otherplaces, in Maddox et al. J Exp. Med., 158:1211 (1983).

Example 63 Identification of PRO317 Receptors

Purified PRO317 is useful for characterization and purification ofspecific cell surface receptors and other binding molecules. Cells whichrespond to PRO317 by metabolic changes or other specific responses arelikely to express a receptor for PRO317. Such receptors include, but arenot limited to, receptors associated with and activated by tyrosine andserine/threonine kinases. See Kolodziejczyk and Hall, supra, for areview on known receptors for the TGF- superfamily. Candidate receptorsfor this superfamily fall into two primary groups, termed type I andtype II receptors. Both types are serine/threonine kinases. Uponactivation by the appropriate ligand, type I and type II receptorsphysically interact to form hetero-oligomers and subsequently activateintracellular signaling cascades, ultimately regulating genetranscription and expression. In addition, TGF- binds to a thirdreceptor class, type III, a membrane-anchored proteoglycan lacking thekinase activity typical of signal transducing molecules.

PRO317 receptors or other PRO317-binding molecules may be identified byinteraction with radiolabeled PRO317. Radioactive labels may beincorporated into PRO317 by various methods known in the art. Apreferred embodiment is the labeling of primary amino groups in PRO317with ¹²⁵I Bolton-Hunter reagent (Bolton and Hunter, Biochem. J., 133:529(1973)), which has been used to label other polypeptides withoutconcomitant loss of biological activity (Hebert et al., J. Biol. Chem.,266:18989 (1991); McColl et al, J. Immunol., 150:4550-4555 (1993)).Receptor-bearing cells are incubated with labeled PRO317. The cells arethen washed to removed unbound PRO317, and receptor-bound PRO317 isquantified. The data obtained using different concentrations of PRO317are used to calculate values for the number and affinity of receptors.

Labeled PRO317 is useful as a reagent for purification of its specificreceptor. In one embodiment of affinity purification, PRO317 iscovalently coupled to a chromatography column. Receptor-bearing cellsare extracted, and the extract is passed over the column. The receptorbinds to the column by virtue of its biological affinity for PRO317. Thereceptor is recovered from the column and subjected to N-terminalprotein sequencing. This amino acid sequence is then used to designdegenerate oligonucleotide probes for cloning the receptor gene.

In an alternative method, mRNA is obtained from receptor-bearing cellsand made into a cDNA library. The library is transfected into apopulation of cells, and those cells expressing the receptor areselected using fluorescently labeled PRO317. The receptor is identifiedby recovering and sequencing recombinant DNA from highly labeled cells.

In another alternative method, antibodies are raised against the surfaceof receptor bearing cells, specifically monoclonal antibodies. Themonoclonal antibodies are screened to identify those which inhibit thebinding of labeled PRO317. These monoclonal antibodies are then used inaffinity purification or expression cloning of the receptor.

Soluble receptors or other soluble binding molecules are identified in asimilar manner. Labeled PRO317 is incubated with extracts or otherappropriate materials derived from the uterus. After incubation, PRO317complexes larger than the size of purified PRO317 are identified by asizing technique such as size-exclusion chromatography or densitygradient centrifugation and are purified by methods known in the art.The soluble receptors or binding protein(s) are subjected to N-terminalsequencing to obtain information sufficient for database identification,if the soluble protein is known, or for cloning, if the soluble proteinis unknown.

Example 64 Determination of PRO317-Induced Cellular Response

The biological activity of PRO317 is measured, for example, by bindingof an PRO317 of the invention to an PRO317 receptor. A test compound isscreened as an antagonist for its ability to block binding of PRO317 tothe receptor. A test compound is screened as an agonist of the PRO317for its ability to bind an PRO317 receptor and influence the samephysiological events as PRO317 using, for example, the KIRA-ELISA assaydescribed by Sadick et al., Analytical Biochemistry, 235:207-214 (1996)in which activation of a receptor tyrosine kinase is monitored byimmuno-capture of the activated receptor and quantitation of the levelof ligand-induced phosphorylation. The assay may be adapted to monitorPRO317-induced receptor activation through the use of an PRO317receptor-specific antibody to capture the activated receptor. Thesetechniques are also applicable to other PRO polypeptides describedherein.

Example 65 Use of PRO224 for Screening Compounds

PRO224 is expressed in a cell stripped of membrane proteins and capableof expressing PRO224. Low density lipoproteins having a detectable labelare added to the cells and incubated for a sufficient time forendocytosis. The cells are washed. The cells are then analysed for labelbound to the membrane and within the cell after cell lysis. Detection ofthe low density lipoproteins within the cell determines that PRO224 iswithin the family of low density lipoprotein receptor proteins. Membersfound within this family are then used for screening compounds whichaffect these receptors, and particularly the uptake of cholesterol viathese receptors.

Example 66 Ability of PRO Polypeptides to Inhibit Vascular EndothelialGrowth Factor (VEGF) Stimulated Proliferation of Endothelial Cell Growth(Assay 9)

The ability of various PRO polypeptides to inhibit VEGF stimulatedproliferation of endothelial cells was tested. Polypeptides testingpositive in this assay are useful for inhibiting endothelial cell growthin mammals where such an effect would be beneficial, e.g., forinhibiting tumor growth.

Specifically, bovine adrenal cortical capillary endothelial cells (ACE)(from primary culture, maximum of 12-14 passages) were plated in 96-wellplates at 500 cells/well per 100 microliter. Assay media included lowglucose DMEM, 10% calf serum, 2 mM glutamine, and1×penicillin/streptomycin/fungizone. Control wells included thefollowing: (1) no ACE cells added; (2) ACE cells alone; (3) ACE cellsplus 5 ng/ml FGF; (4) ACE cells plus 3 ng/ml VEGF; (5) ACE cells plus 3ng/ml VEGF plus 1 ng/ml TGF-beta; and (6) ACE cells plus 3 ng/ml VEGFplus 5 ng/ml LIF. The test samples, poly-his tagged PRO polypeptides (in100 microliter volumes), were then added to the wells (at dilutions of1%, 0.1% and 0.01%, respectively). The cell cultures were incubated for6-7 days at 37° C./5% CO₂. After the incubation, the media in the wellswas aspirated, the cells were washed 1× with PBS. An acid phosphatasereaction mixture (100 microliter; 0.1M sodium acetate, pH 5.5, 0.1%Triton X-100, 10 mM p-nitrophenyl phosphate) was then added to eachwell. After a 2 hour incubation at 37° C., the reaction was stopped byaddition of 10 microliters 1N NaOH. Optical density (OD) was measured ona microplate reader at 405 nm.

The activity of PRO polypeptides was calculated as the percentinhibition of VEGF (3 ng/ml) stimulated proliferation (as determined bymeasuring acid phosphatase activity at OD 405 nm) relative to the cellswithout stimulation. TGF-beta was employed as an activity reference at 1ng/ml, since TGF-beta blocks 70-90% of VEGF-stimulated ACE cellproliferation. The results are indicative of the utility of the PROpolypeptides in cancer therapy and specifically in inhibiting tumorangiogenesis. Numerical values (relative inhibition) are determined bycalculating the percent inhibition of VEGF stimulated proliferation bythe PRO polypeptides relative to cells without stimulation and thendividing that percentage into the percent inhibition obtained by TGF-βat 1 ng/ml which is known to block 70-90% of VEGF stimulated cellproliferation. The results are considered positive if the PROpolypeptide exhibits 30% or greater inhibition of VEGF stimulation ofendothelial cell growth (relative inhibition 30% or greater).

The following polypeptides tested positive in this assay: PRO211,PRO217, PRO187, PRO219, PRO246, PRO228, PRO245, PRO221, PRO258, PRO301,PRO224, PRO272, PRO328, PRO331, PRO224, PRO328, PRO272, PRO301, PRO331and PRO214.

Example 67 Retinal Neuron Survival (Assay 52)

This example demonstrates that certain PRO polypeptides have efficacy inenhancing the survival of retinal neuron cells and, therefore, areuseful for the therapeutic treatment of retinal disorders or injuriesincluding, for example, treating sight loss in mammals due to retinitispigmentosum, AMD, etc.

Sprague Dawley rat pups at postnatal day 7 (mixed population: glia andretinal neuronal types) are killed by decapitation following CO₂anesthesia and the eyes are removed under sterile conditions. The neuralretina is dissected away from the pigment epithelium and other oculartissue and then dissociated into a single cell suspension using 0.25%trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. for7-10 minutes after which the trypsin is inactivated by adding 1 mlsoybean trypsin inhibitor. The cells are plated at 100,000 cells perwell in 96 well plates in DMEM/F12 supplemented with N2 and with orwithout the specific test PRO polypeptide. Cells for all experiments aregrown at 37° C. in a water saturated atmosphere of 5% CO₂. After 2-3days in culture, cells are stained with calcein AM then fixed using 4%paraformaldehyde and stained with DAPI for determination of total cellcount. The total cells (fluorescent) are quantified at 20× objectivemagnification using CCD camera and NIH image software for MacIntosh.Fields in the well are chosen at random.

The effect of various concentration of PRO polypeptides are reportedherein where percent survival is calculated by dividing the total numberof calcein AM positive cells at 2-3 days in culture by the total numberof DAPI-labeled cells at 2-3 days in culture. Anything above 30%survival is considered positive.

The following PRO polypeptides tested positive in this assay usingpolypeptide concentrations within the range of 0.01% to 1.0% in theassay: PRO220 and PRO346.

Example 68 Rod Photoreceptor Cell Survival (Assay 56)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinal disordersor injuries including, for example, treating sight loss in mammals dueto retinitis pigmentosum, AMD, etc. Sprague Dawley rat pups at 7 daypostnatal (mixed population: glia and retinal neuronal cell types) arekilled by decapitation following CO₂ anesthesis and the eyes are removedunder sterile conditions. The neural retina is dissected away form thepigment epithelium and other ocular tissue and then dissociated into asingle cell suspension using 0.25% trypsin in Ca²⁺, Mg²⁺-free PBS. Theretinas are incubated at 37° C. for 7-10 minutes after which the trypsinis inactivated by adding 1 ml soybean trypsin inhibitor. The cells areplated at 100,000 cells per well in 96 well plates in DMEM/F12supplemented with N₂. Cells for all experiments are grown at 37° C. in awater saturated atmosphere of 5% CO₂. After 2-3 days in culture, cellsare fixed using 4% paraformaldehyde, and then stained using CellTrackerGreen CMFDA. Rho 4D2 (ascites or IgG 1:100), a monoclonal antibodydirected towards the visual pigment rhodopsin is used to detect rodphotoreceptor cells by indirect immunofluorescence. The results arecalculated as % survival: total number of calcein - rhodopsin positivecells at 2-3 days in culture, divided by the total number of rhodopsinpositive cells at time 2-3 days in culture. The total cells(fluorescent) are quantified at 20×objective magnification using a CCDcamera and NIH image software for MacIntosh. Fields in the well arechosen at random.

The following polypeptides tested positive in this assay: PRO220 andPRO346.

Example 69 Induction of Endothelial Cell Apoptosis (Assay 73)

The ability of PRO polypeptides to induce apoptosis in endothelial cellswas tested in human venous umbilical vein endothelial cells (HUVEC, CellSystems). A positive test in the assay is indicative of the usefulnessof the polypeptide in therapeutically treating tumors as well asvascular disorders where inducing apoptosis of endothelial cells wouldbe beneficial.

The cells were plated on 96-well microtiter plates (Amersham LifeScience, cytostar-T scintillating microplate, RPNQ160, sterile,tissue-culture treated, individually wrapped), in 10% serum (CSG-medium,Cell Systems), at a density of 2×10⁴ cells per well in a total volume of100 μl. On day 2, test samples containing the PRO polypeptide were addedin triplicate at dilutions of 1%, 0.33% and 0.11%. Wells without cellswere used as a blank and wells with cells only were used as a negativecontrol. As a positive control 1:3 serial dilutions of 50 μl of a3×stock of staurosporine were used. The ability of the PRO polypeptideto induce apoptosis was determined by processing of the 96 well platesfor detection of Annexin V, a member of the calcium and phospholipidbinding proteins, to detect apoptosis.

0.2 ml Annexin V—Biotin stock solution (100 μg/ml) was diluted in 4.6 ml2×Ca²⁺ binding buffer and 2.5% BSA (1:25 dilution). 50 μl of the dilutedAnnexin V—Biotin solution was added to each well (except controls) to afinal concentration of 1.0 μg/ml. The samples were incubated for 10-15minutes with Annexin-Biotin prior to direct addition of³⁵S-Streptavidin. ³⁵S-Streptavidin was diluted in 2×Ca²⁺ Binding buffer,2.5% BSA and was added to all wells at a final concentration of 3×10⁴cpm/well. The plates were then sealed, centrifuged at 1000 rpm for 15minutes and placed on orbital shaker for 2 hours. The analysis wasperformed on a 1450 Microbeta Trilux (Wallac). Percent above backgroundrepresents the percentage amount of counts per minute above the negativecontrols. Percents greater than or equal to 30% above background areconsidered positive.

The following PRO polypeptides tested positive in this assay: PRO228,PRO217 and PRO301.

Example 70 PDB12 Cell Inhibition (Assay 40)

This example demonstrates that various PRO polypeptides have efficacy ininhibiting protein production by PDB12 pancreatic ductal cells and are,therefore, useful in the therapeutic treatment of disorders whichinvolve protein secretion by the pancreas, including diabetes, and thelike.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 wellplates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100μL of growth media with the PRO polypeptide test sample or negativecontrol lacking the PRO polypeptide is then added to well, for a finalvolume of 200 μL. Controls contain growth medium containing a proteinshown to be inactive in this assay. Cells are incubated for 4 days at37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and theflourescent reading is measured at 4 hours post addition of AB, on amicrotiter plate reader at 530 nm excitation and 590 nm emission. Thestandard employed is cells without Bovine Pituitary Extract (BPE) andwith various concentrations of BPE. Buffer or CM controls from unknownsare run 2 times on each 96 well plate.

These assays allow one to calculate a percent decrease in proteinproduction by comparing the Alamar Blue Dye calculated proteinconcentration produced by the PRO polypeptide-treated cells with theAlamar Blue Dye calculated protein concentration produced by thenegative control cells. A percent decrease in protein production ofgreater than or equal to 25% as compared to the negative control cellsis considered positive.

The following polypeptides tested positive in this assay: PRO211,PRO287, PRO301 and PRO293.

Example 71 Stimulation of Adult Heart Hypertrophy (Assay 2)

This assay is designed to measure the ability of various PROpolypeptides to stimulate hypertrophy of adult heart. PRO polypeptidestesting positive in this assay would be expected to be useful for thetherapeutic treatment of various cardiac insufficiency disorders.

Ventricular myocytes freshly isolated from adult (250 g) Sprague Dawleyrats are plated at 2000 cell/well in 180 μl volume. Cells are isolatedand plated on day 1, the PRO polypeptide-containing test samples orgrowth medium only (negative control) (20 μl volume) is added on day 2and the cells are then fixed and stained on day 5. After staining, cellsize is visualized wherein cells showing no growth enhancement ascompared to control cells are given a value of 0.0, cells showing smallto moderate growth enhancement as compared to control cells are given avalue of 1.0 and cells showing large growth enhancement as compared tocontrol cells are given a value of 2.0. Any degree of growth enhancementas compared to the negative control cells is considered positive for theassay.

The following PRO polypeptides tested positive in this assay: PRO287,PRO301, PRO293 and PRO303.

Example 72 PDB12 Cell Proliferation (Assay 29)

This example demonstrates that various PRO polypeptides have efficacy ininducing proliferation of PDB12 pancreatic ductal cells and are,therefore, useful in the therapeutic treatment of disorders whichinvolve protein secretion by the pancreas, including diabetes, and thelike.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 wellplates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100μL of growth media with the PRO polypeptide test sample or negativecontrol lacking the PRO polypeptide is then added to well, for a finalvolume of 200 μL. Controls contain growth medium containing a proteinshown to be inactive in this assay. Cells are incubated for 4 days at37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and theflourescent reading is measured at 4 hours post addition of AB, on amicrotiter plate reader at 530 nm excitation and 590 nm emission. Thestandard employed is cells without Bovine Pituitary Extract (BPE) andwith various concentrations of BPE. Buffer or growth medium onlycontrols from unknowns are run 2 times on each 96 well plate.

Percent increase in protein production is calculated by comparing theAlamar Blue Dye calculated protein concentration produced by the PROpolypeptide-treated cells with the Alamar Blue Dye calculated proteinconcentration produced by the negative control cells. A percent increasein protein production of greater than or equal to 25% as compared to thenegative control cells is considered positive.

The following PRO polypeptides tested positive in this assay: PRO301 andPRO303.

Example 73 Enhancement of Heart Neonatal Hypertrophy (Assay 1)

This assay is designed to measure the ability of PRO polypeptides tostimulate hypertrophy of neonatal heart. PRO polypeptides testingpositive in this assay are expected to be useful for the therapeutictreatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 μl at 7.5×10⁴/ml, serum <0.1%, freshly isolated)are added on day 1 to 96-well plates previously coated with DMEM/F12+4%FCS. Test samples containing the test PRO polypeptide or growth mediumonly (hegative control) (20 μl/well) are added directly to the wells onday 1. PGF (20 μl/well) is then added on day 2 at final concentration of10⁻⁶ M. The cells are then stained on day 4 and visually scored on day5, wherein cells showing no increase in size as compared to negativecontrols are scored 0.0, cells showing a small to moderate increase insize as compared to negative controls are scored 1.0 and cells showing alarge increase in size as compared to negative controls are scored 2.0.A positive result in the assay is a score of 1.0 or greater.

The following polypeptides tested positive in this assay: PRO224 andPRO231.

Example 74 Stimulatory Activity in Mixed Lymphocyte Reaction (MLR) Assay(Assay 24)

This example shows that certain polypeptides of the invention are activeas a stimulator of the proliferation of stimulated T-lymphocytes.Compounds which stimulate proliferation of lymphocytes are usefultherapeutically where enhancement of an immune response is beneficial. Atherapeutic agent may take the form of antagonists of the polypeptide ofthe invention, for example, murine-human chimeric, humanized or humanantibodies against the polypeptide.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO₂) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutaline, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgG isused as the control. The wells are then incubated at 37° C., 5% CO₂ for4 days. On day 5, each well is pulsed with tritiated thymidine (1.0mC/well; Amersham). After 6 hours the cells are washed 3 times and thenthe uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI; 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Positive increases over control are considered positive with increasesof greater than or equal to 180% being preferred. However, any valuegreater than control indicates a stimulatory effect for the testprotein.

The following PRO polypeptides tested positive in this assay: PRO245,PRO269, PRO217, PRO301, PRO266, PRO335, PRO331, PRO533 and PRO326.

Example 75 Pericyte c-Fos Induction (Assay 93)

This assay shows that certain polypeptides of the invention act toinduce the expression of c-fos in pericyte cells and, therefore, areuseful not only as diagnostic markers for particular types ofpericyte-associated tumors but also for giving rise to antagonists whichwould be expected to be useful for the therapeutic treatment ofpericyte-associated tumors. Specifically, on day 1, pericytes arereceived from VEC Technologies and all but 5 ml of media is removed fromflask. On day 2, the pericytes are trypsinized, washed, spun and thenplated onto 96 well plates. On day 7, the media is removed and thepericytes are treated with 100 μl of PRO polypeptide test samples andcontrols (positive control=DME+5% serum +/−PDGF at 500 ng/ml; negativecontrol=protein 32). Replicates are averaged and SD/CV are determined.Fold increase over Protein 32 (buffer control) value indicated bychemiluminescence units (RLU) luminometer reading verses frequency isplotted on a histogram. Two-fold above Protein 32 value is consideredpositive for the assay. ASY Matrix: Growth media=low glucose DMEM=20%FBS+1×pen strep+1×fungizone. Assay Media=low glucose DMEM+5% FBS.

The following polypeptides tested positive in this assay: PRO214,PRO219, PRO221 and PRO224.

Example 76 Ability of PRO Polypeptides to Stimulate the Release ofProteoglycans from Cartilage (Assay 97)

The ability of various PRO polypeptides to stimulate the release ofproteoglycans from cartilage tissue was tested as follows.

The metacarphophalangeal joint of 4-6 month old pigs was asepticallydissected, and articular cartilage was removed by free hand slicingbeing careful to avoid the underlying bone. The cartilage was minced andcultured in bulk for 24 hours in a humidified atmosphere of 95% air, 5%CO₂ in serum free (SF) media (DME/F121:1) woth 0.1% BSA and 100 U/mlpenicillin and 100 μg/ml streptomycin. After washing three times,approximately 100 mg of articular cartilage was aliquoted into micronicstubes and incubated for an additional 24 hours in the above SF media.PRO polypeptides were then added at 1% either alone or in combinationwith 18 ng/ml interleukin-1α, a known stimulator of proteoglycan releasefrom cartilage tissue. The supernatant was then harvested and assayedfor the amount of proteoglycans using the 1,9-dimethyl-methylene blue(DMB) calorimetric assay (Farndale and Buttle, Biochem. Biophys. Acta883:173-177 (1985)). A positive result in this assay indicates that thetest polypeptide will find use, for example, in the treatment ofsports-related joint problems, articular cartilage defects,osteoarthritis or rheumatoid arthritis.

When various PRO polypeptides were tested in the above assay, thepolypeptides demonstrated a marked ability to stimulate release ofproteoglycans from cartilage tissue both basally and after stimulationwith interleukin-1α and at 24 and 72 hours after treatment, therebyindicating that these PRO polypeptides are useful for stimulatingproteoglycan release from cartilage tissue. As such, these PROpolypeptides are useful for the treatment of sports-related jointproblems, articular cartilage defects, osteoarthritis or rheumatoidarthritis. The polypeptides testing positive in this assay are: PRO211.

Example 77 Skin Vascular Permeability Assay (Assay 64)

This assay shows that certain polypeptides of the invention stimulate animmune response and induce inflammation by inducing mononuclear cell,eosinophil and PMN infiltration at the site of injection of the animal.Compounds which stimulate an immune response are useful therapeuticallywhere stimulation of an immune response is beneficial. This skinvascular permeability assay is conducted as follows. Hairless guineapigs weighing 350 grams or more are anesthetized with ketamine (75-80mg/Kg) and 5 mg/Kg xylazine intramuscularly (IM). A sample of purifiedpolypeptide of the invention or a conditioned media test sample isinjected intradermally onto the backs of the test animals with 100 μlper injection site. It is possible to have about 10-30, preferably about16-24, injection sites per animal. One μl of Evans blue dye (1% inphysiologic buffered saline) is injected intracardially. Blemishes atthe injection sites are then measured (mm diameter) at 1 hr and 6 hrpost injection. Animals were sacrificed at 6 hrs after injection. Eachskin injection site is biopsied and fixed in formalin. The skins arethen prepared for histopathologic evaluation. Each site is evaluated forinflammatory cell infiltration into the skin. Sites with visibleinflammatory cell inflammation are scored as positive. Inflammatorycells may be neutrophilic, eosinophilic, monocytic or lymphocytic. Atleast a minimal perivascular infiltrate at the injection site is scoredas positve, no infiltrate at the site of injection is scored asnegative.

The following polypeptides tested positive in this assay: PRO245,PRO217, PRO326, PRO266, PRO272, PRO301, PRO331 and PRO335.

Example 78 Enhancement of Heart Neonatal Hypertrophy Induced by F2a(Assay 37)

This assay is designed to measure the ability of PRO polypeptides tostimulate hypertrophy of neonatal heart. PRO polypeptides testingpositive in this assay are expected to be useful for the therapeutictreatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 μl at 7.5×10⁴/ml, serum <0.1%, freshly isolated)are added on day 1 to 96-well plates previously coated with DMEM/F12+4%FCS. Test samples containing the test PRO polypeptide (20 μl/well) areadded directly to the wells on day 1. PGF (20 μl/well) is then added onday 2 at a final concentration of 10⁻⁶ M. The cells are then stain onday 4 and visually scored on day 5. Visual scores are based on cellsize, wherein cells showing no increase in size as compared to negativecontrols are scored 0.0, cells showing a small to moderate increase insize as compared to negative controls are scored 1.0 and cells showing alarge increase in size as compared to negative controls are scored 2.0.A score of 1.0 or greater is considered positive.

No PBS is included, since calcium concentration is critical for assayresponse. Plates are coated with DMEM/F12 plus 4% FCS (200 μl/well).Assay media included: DMEM/F12 (with 2.44 gm bicarbonate), μg/mltransferrin, 1 μg/ml insulin, 1 μg/ml aprotinin, 2 mmol/L glutamine, 100U/ml penicillin G, 100 μg/ml streptomycin. Protein buffer containingmannitol (4%) gave a positive signal (score 3.5) at 1/10 (0.4%) and1/100 (0.04%), but not at 1/1000 (0.004%). Therefore the test samplebuffer containing mannitol is not run.

The following PRO polypeptides tested positive in this assay: PRO224.

Example 79 Inhibitory Activity in Mixed Lymphocyte Reaction (MLR) Assay(Assay 67)

This example shows that one or more of the polypeptides of the inventionare active as inhibitors of the proliferation of stimulatedT-lymphocytes. Compounds which inhibit proliferation of lymphocytes areuseful therapeutically where suppression of an immune response isbeneficial.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO2) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgG isused as the control. The wells are then incubated at 37° C., 5% CO₂ for4 days. On day 5, each well is pulsed with tritiated thymidine (1.0mC/well; Amersham). After 6 hours the cells are washed 3 times and thenthe uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI; 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Any decreases below control is considered to be a positive result for aninhibitory compound, with decreases of less than or equal to 80% beingpreferred. However, any value less than control indicates an inhibitoryeffect for the test protein.

The following polypeptide tested positive in this assay: PRO235, PRO245and PRO332.

Example 80 Induction of Endothelial Cell Apoptosis (ELISA) (Assay 109)

The ability of PRO polypeptides to induce apoptosis in endothelial cellswas tested in human venous umbilical vein endothelial cells (HUVEC, CellSystems) using a 96-well format, in 0% serum media supplemented with 100ng/ml VEGF, 0.1% BSA, 1×penn/strep. A positive result in this assayindicates the usefulness of the polypeptide for therapeutically treatingany of a variety of conditions associated with undesired endothelialcell growth including, for example, the inhibition of tumor growth. The96-well plates used were manufactured by Falcon (No. 3072). Coating of96 well plates were prepared by allowing gelatinization to occur for >30minutes with 100 μl of 0.2% gelatin in PBS solution. The gelatin mix wasaspirated thoroughly before plating HUVEC cells at a final concentrationof 2×10⁴ cells/ml in 10% serum containing medium—100 μl volume per well.The cells were grown for 24 hours before adding test samples containingthe PRO polypeptide of interest.

To all wells, 100 μl of 0% serum media (Cell Systems) complemented with100 ng/ml VEGF, 0.1% BSA, 1×penn/strep was added. Test samplescontaining PRO polypeptides were added in triplicate at dilutions of 1%,0.33% and 0.11%. Wells without cells were used as a blank and wells withcells only were used as a negative control. As a positive control, 1:3serial dilutions of 50 μl of a 3×stock of staurosporine were used. Thecells were incubated for 24 to 35 hours prior to ELISA.

ELISA was used to determine levels of apoptosis preparing solutionsaccording to the Boehringer Manual [Boehringer, Cell Death DetectionELISA plus, Cat No. 1 920 685]. Sample preparations: 96 well plates werespun down at 1 krpm for 10 minutes (200 g); the supernatant was removedby fast inversion, placing the plate upside down on a paper towel toremove residual liquid. To each well, 200 μl of 1×Lysis buffer was addedand incubation allowed at room temperature for 30 minutes withoutshaking. The plates were spun down for 10 minutes at 1 krpm, and 20 μlof the lysate (cytoplasmic fraction) was transferred into streptavidincoated MTP. 80 μl of immunoreagent mix was added to the 20 μl lystate ineach well. The MTP was covered with adhesive foil and incubated at roomtemperature for 2 hours by placing it on an orbital shaker (200 rpm).After two hours, the supernatant was removed by suction and the wellsrinsed three times with 250 μl of 1×incubation buffer per well (removedby suction). Substrate solution was added (100 μl) into each well andincubated on an orbital shaker at room temperature at 250 rpm untilcolor development was sufficient for a photometric analysis (approx.after 10-20 minutes). A 96 well reader was used to read the plates at405 nm, reference wavelength, 492 nm. The levels obtained for PIN 32(control buffer) was set to 100%. Samples with levels >130% wereconsidered positive for induction of apoptosis.

The following PRO polypeptides tested positive in this assay: PRO235.

Example 81 Human Venous Endothelial Cell Calcium Flux Assay (Assay 68)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to stimulate calcium flux in humanumbilical vein endothelial cells (HUVEC, Cell Systems). Calcium influxis a well documented response upon binding of certain ligands to theirreceptors. A test compound that results in a positive response in thepresent calcium influx assay can be said to bind to a specific receptorand activate a biological signaling pathway in human endothelial cells.This could ultimately lead, for example, to endothelial cell division,inhibition of endothelial cell proliferation, endothelial tubeformation, cell migration, apoptosis, etc.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50:50 without glycine, 1% glutamine, 10 mM Hepes, 10% FBS,10 ng/ml bFGF), were plated on 96-well microtiter ViewPlates-96 (PackardInstrument Company Part #6005182) microtiter plates at a cell density of2×10⁴ cells/well. The day after plating, the cells were washed threetimes with buffer (HBSS plus 10 mM Hepes), leaving 100 μl/well. Then 100μl/well of 8 μM Fluo-3 (2×) was added. The cells were incubated for 1.5hours at 37° C./5% CO₂. After incubation, the cells were then washed3×with buffer (described above) leaving 100 μl/well. Test samples of thePRO polypeptides were prepared on different 96-well plates at5×concentration in buffer. The positive control corresponded to 50 μMionomycin (5×); the negative control corresponded to Protein 32. Cellplate and sample plates were run on a FLIPR (Molecular Devices) machine.The FLIPR machine added 25 μl of test sample to the cells, and readingswere taken every second for one minute, then every 3 seconds for thenext three minutes.

The fluorescence change from baseline to the maximum rise of the curve(Δ change) was calculated, and replicates averaged. The rate offluorescence increase was monitored, and only those samples which had aΔ change greater than 1000 and a rise within 60 seconds, were consideredpositive.

The following PRO polypeptides tested positive in the present assay:PRO245.

Example 82 Fibroblast (BHK-21) Proliferation (Assay 98)

This assay shows that certain PRO polypeptides of the invention act toinduce proliferation of mammalian fibroblast cells in culture and,therefore, function as useful growth factors in mammalian systems. Theassay is performed as follows. BHK-21 fibroblast cells plated instandard growth medium at 2500 cells/well in a total volume of 100 μl.The PRO polypeptide, β-FGF (positive control) or nothing (negativecontrol) are then added to the wells in the presence of 1 μg/ml ofheparin for a total final volume of 200 μl. The cells are then incubatedat 37° C. for 6 to 7 days. After incubation, the media is removed, thecells are washed with PBS and then an acid phosphatase substratereaction mixture (100 μl/well) is added. The cells are then incubated at37° C. for 2 hours. 10 μL per well of 1N NaOH is then added to stop theacid phosphatase reaction. The plates are then read at OD 405 nm. Apositive in the assay is acid phosphatase activity which is at least 50%above the negative control.

The following PRO polypeptide tested positive in this assay: PRO258.

Example 83 Inhibition of Heart Adult Hypertrophy (Assay 42)

This assay is designed to measure the inhibition of heart adulthypertrophy. PRO polypeptides testing positive in this assay may finduse in the therapeutic treatment of cardiac disorders associated withcardiac hypertrophy.

Ventricular myocytes are freshly isolated from adult (250 g) HarlanSprague Dawley rats and the cells are plated at 2000/well in 180 μlvolume. On day two, test samples (20 μL) containing the test PROpolypeptide are added. On day five, the cells are fixed and thenstained. An increase in ANP message can also be measured by PCR fromcells after a few hours. Results are based on a visual score of cellsize: 0=no inhibition, −1=small inhibition, −2=large inhibition. A scoreof less than 0 is considered positive. Activity reference corresponds tophenylephrin (PE) at 0.1 mM, as a positive control. Assay mediaincluded: M199 (modified)-glutamine free, NaHCO₃, phenol red,supplemented with 100 nM insulin, 0.2% BSA, 5 mM cretine, 2 mML-carnitine, 5 mM taurine, 100 U/ml penicillin G, 100 μg/ml streptomycin(CCT medium). Only inner 60 wells are used in 96 well plates. Of these,6 wells are reserved for negative and positive (PE) controls.

The following PRO polypeptides provided a score of less than 0 in theabove assay: PRO269.

Example 84 Induction of c-fos in Endothelial Cells (Assay 34)

This assay is designed to determine whether PRO polypeptides show theability to induce c-fos in endothelial cells. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of conditions or disorders where angiogenesiswould be beneficial including, for example, wound healing, and the like(as would agonists of these PRO polypeptides). Antagonists of the PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of cancerous tumors.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50% Ham's F12 w/o GHT: low glucose, and 50% DMEM withoutglycine: with NaHCO3, 1% glutamine, 10 mM HEPES, 10% FBS, 10 ng/ml bFGF)were plated on 96-well microtiter plates at a cell density of 1×10⁴cells/well. The day after plating, the cells were starved by removingthe growth media and treating the cells with 100 μl/well test samplesand controls (positive control=growth media; negative control =Protein32 buffer=10 mM HEPES, 140 mM NaCl, 4% (w/v) mannitol, pH 6.8). Thecells were incubated for 30 minutes at 37° C, in 5% CO₂. The sampleswere removed, and the first part of the bDNA kit protocol (ChironDiagnostics, cat. #6005-037) was followed, where each capitalizedreagent/buffer listed below was available from the kit.

Briefly, the amounts of the TM Lysis Buffer and Probes needed for thetests were calculated based on information provided by the manufacturer.The appropriate amounts of thawed Probes were added to the TM LysisBuffer. The Capture Hybridization Buffer was warmed to room temperature.The bDNA strips were set up in the metal strip holders, and 100 μl ofCapture Hybridization Buffer was added to each b-DNA well needed,followed by incubation for at least 30 minutes. The test plates with thecells were removed from the incubator, and the media was gently removedusing the vacuum manifold. 100 μl of Lysis Hybridization Buffer withProbes were quickly pipetted into each well of the microtiter plates.The plates were then incubated at 55° C. for 15 minutes. Upon removalfrom the incubator, the plates were placed on the vortex mixer with themicrotiter adapter head and vortexed on the #2 setting for one minute.80 μl of the lysate was removed and added to the bDNA wells containingthe Capture Hybridization Buffer, and pipetted up and down to mix. Theplates were incubated at 53° C. for at least 16 hours.

On the next day, the second part of the bDNA kit protocol was followed.Specifically, the plates were removed from the incubator and placed onthe bench to cool for 10 minutes. The volumes of additions needed werecalculated based upon information provided by the manufacturer. AnAmplifier Working Solution was prepared by making a 1:100 dilution ofthe Amplifier Concentrate (20 fm/μl) in AL Hybridization Buffer. Thehybridization mixture was removed from the plates and washed twice withWash A. 50 μl of Amplifier Working Solution was added to each well andthe wells were incubated at 53° C. for 30 minutes. The plates were thenremoved from the incubator and allowed to cool for 10 minutes. The LabelProbe Working Solution was prepared by making a 1:100 dilution of LabelConcentrate (40 pmoles/μl) in AL Hybridization Buffer. After the10-minute cool-down period, the amplifier hybridization mixture wasremoved and the plates were washed twice with Wash A. 50 μl of LabelProbe Working Solution was added to each well and the wells wereincubated at 53° C. for 15 minutes. After cooling for 10 minutes, theSubstrate was warmed to room temperature. Upon addition of 3 μl ofSubstrate Enhancer to each ml of Substrate needed for the assay, theplates were allowed to cool for 10 minutes, the label hybridizationmixture was removed, and the plates were washed twice with Wash A andthree times with Wash D. 50 μl of the Substrate Solution with Enhancerwas added to each well. The plates were incubated for 30 minutes at 37°C. and RLU was read in an appropriate luminometer.

The replicates were averaged and the coefficient of variation wasdetermined. The measure of activity of the fold increase over thenegative control (Protein 32/HEPES buffer described above) value wasindicated by chemiluminescence units (RLU). The results are consideredpositive if the PRO polypeptide exhibits at least a two-fold value overthe negative buffer control. Negative control=1.00 RLU at 1.00%dilution. Positive control=8.39 RLU at 1.00% dilution.

The following PRO polypeptides tested positive in this assay: PRO287.

Example 85 Guinea Pig Vascular Leak (Assays 32 and 51)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce vascular permeability.Polypeptides testing positive in this assay are expected to be usefulfor the therapeutic treatment of conditions which would benefit fromenhanced vascular permeability including, for example, conditions whichmay benefit from enhanced local immune system cell infiltration.

Hairless guinea pigs weighing 350 grams or more were anesthetized withKetamine (75-80 mg/kg) and 5 mg/kg Xylazine intramuscularly. Testsamples containing the PRO polypeptide or a physiological buffer withoutthe test polypeptide are injected into skin on the back of the testanimals with 100 μl per injection site intradermally. There wereapproximately 16-24 injection sites per animal. One ml of Evans blue dye(1% in PBS) is then injected intracardially. Skin vascular permeabilityresponses to the compounds (i. e., blemishes at the injection sites ofinjection) are visually scored by measuring the diameter (in mm) ofblue-colored leaks from the site of injection at 1 and 6 hours postadministration of the test materials. The mm diameter of blueness at thesite of injection is observed and recorded as well as the severity ofthe vascular leakage. Blemishes of at least 5 mm in diameter areconsidered positive for the assay when testing purified proteins, beingindicative of the ability to induce vascular leakage or permeability. Aresponse greater than 7 mm diameter is considered positive forconditioned media samples. Human VEGF at 0.1 μg/100 μl is used as apositive control, inducing a response of 15-23 mm diameter.

The following PRO polypeptides tested positive in this assay: PRO302 andPRO533.

Example 86 Detection of Endothelial Cell Apoptosis (FACS) (Assay 96)

The ability of PRO polypeptides of the present invention to induceapoptosis in endothelial cells was tested in human venous umbilical veinendothelial cells (HUVEC, Cell Systems) in gelatinized T175 flasks usingHUVEC cells below passage 10. PRO polypeptides testing positive in thisassay are expected to be useful for therapeutically treating conditionswhere apoptosis of endothelial cells would be beneficial including, forexample, the therapeutic treatment of tumors.

On day one, the cells were split [420,000 cells per gelatinized 6 cmdishes—(11×10³ cells/cm² Falcon, Primaria)] and grown in mediacontaining serum (CS-C, Cell System) overnight or for 16 hours to 24hours.

On day 2, the cells were washed 1× with 5 ml PBS; 3 ml of 0% serummedium was added with VEGF (100 ng/ml); and 30 μl of the PRO testcompound (final dilution 1%) or 0% serum medium (negative control) wasadded. The mixtures were incubated for 48 hours before harvesting.

The cells were then harvested for FACS analysis. The medium wasaspirated and the cells washed once with PBS. 5 ml of 1×trypsin wasadded to the cells in a T-175 flask, and the cells were allowed to standuntil they were released from the plate (about 5-10 minutes).Trypsinization was stopped by adding 5 ml of growth media. The cellswere spun at 1000 rpm for 5 minutes at 4° C. The media was aspirated andthe cells were resuspended in 10 ml of 10% serum complemented medium(Cell Systems), 5 μl of Annexin-FITC (BioVison) added and chilled tubeswere submitted for FACS. A positive result was determined to be enhancedapoptosis in the PRO polypeptide treated samples as compared to thenegative control.

The following PRO polypeptides tested positive in this assay: PRO331.

Example 87 Induction of c-fos in Cortical Neurons (Assay 83)

This assay is designed to determine whether PRO polypeptides show theability to induce c-fos in cortical neurons. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of nervous system disorders and injuries whereneuronal proliferation would be beneficial.

Cortical neurons are dissociated and plated in growth medium at 10,000cells per well in 96 well plates. After approximately 2 cellulardivisions, the cells are treated for 30 minutes with the PRO polypeptideor nothing (negative control). The cells are then fixed for 5 minuteswith cold methanol and stained with an antibody directed againstphosphorylated CREB. mRNA levels are then calculated usingchemiluminescence. A positive in the assay is any factor that results inat least a 2-fold increase in c-fos message as compared to the negativecontrols.

The following PRO polypeptides tested positive in this assay: PRO229 andPRO269.

Example 88 Stimulation of Endothelial Tube Formation (Assay 85)

This assay is designed to determine whether PRO polypeptides show theability to promote endothelial vacuole and lumen formation in theabsence of exogenous growth factors. PRO polypeptides testing positivein this assay would be expected to be useful for the therapeutictreatment of disorders where endothelial vacuole and/or lumen formationwould be beneficial including, for example, where the stimulation ofpinocytosis, ion pumping, vascular permeability and/or junctionalformation would be beneficial.

HUVEC cells (passage <8 from primary) are mixed with type I rat tailcollagen (final concentration 2.6 mg/ml) at a density of 6×10⁵ cells perml and plated at 50 μl per well of M199 culture media supplement with 1%FBS and 1 μM 6-FAM-FITC dye to stain the vacuoles while they are formingand in the presence of the PRO polypeptide. The cells are then incubatedat 37° C./5% CO₂ for 48 hours, fixed with 3.7% formalin room temperaturefor 10 minutes, washed 5 times with M199 medium and then stained withRh-Phalloidin at 4° C. overnight followed by nuclear staining with 4 μMDAPI. A positive result in the assay is when vacuoles are present ingreater than 50% of the cells.

The following PRO polypeptides tested positive in this assay: PRO230.

Example 89 Detection of Polypeptides That Affect Glucose and/or FFAUptake in Skeletal Muscle (Assay 106)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by skeletal muscle cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by skeletal muscle would bebeneficial including, for example, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat differentiated skeletal muscle, and allowed to incubate overnight.Then fresh media with the PRO polypeptide and +/− insulin are added tothe wells. The sample media is then monitored to determine glucose andFFA uptake by the skeletal muscle cells. The insulin will stimulateglucose and FFA uptake by the skeletal muscle, and insulin in mediawithout the PRO polypeptide is used as a positive control, and a limitfor scoring. As the PRO polypeptide being tested may either stimulate orinhibit glucose and FFA uptake, results are scored as positive in theassay if greater than 1.5 times or less than 0.5 times the insulincontrol.

The following PRO polypeptides tested positive as either stimulators orinhibitors of glucose and/or FFA uptake in this assay: PRO187, PRO211,PRO221, PRO222, PRO224, PRO230, PRO239, PRO231, PRO245, PRO247, PRO258,PRO269, PRO328 and PRO533.

Example 90 Rod Photoreceptor Cell Survival Assay (Assay 46)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinal disordersor injuries including, for example, treating sight loss in mammals dueto retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups (postnatal day 7, mixed population: glia andnetinal neural cell types) are killed by decapitation following CO₂anesthesia and the eyes removed under sterile conditions. The neuralretina is dissected away from the pigment epithelium and other oculartissue and then dissociated into a single cell suspension using 0.25%trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. inthis solution for 7-10 minutes after which the trypsin is inactivated byadding 1 ml soybean trypsin inhibitor. The cells are plated at a densityof approximately 10, 000 cells/ml into 96 well plates in DMEM/F12supplemented with N₂. Cells for all experiments are grown at 37° C. in awater saturated atmosphere of 5% CO₂. After 7-10 days in culture, thecells are stained using calcein AM or CellTracker Green CMFDA and thenfixed using 4% paraformaldehyde. Rho 4D2 (ascities or IgG 1:100)monoclonal antibody directed towards the visual pigment rhodopsin isused to detect rod photoreceptor cells by indirect immunofluorescence.The results are calculated as % survival: total number ofcalcein—rhodopsin positive cells at 7-10 days in culture, divided by thetotal number of rhodopsin positive cells at time 7-10 days in culture.The total cells (fluorescent) are quantified at 20×objectivemagnification using a CCD camera and NIH image software for MacIntosh.Fields in the well are chosen at random.

The following polypeptides tested positive in this assay: PRO245.

Example 91 In Vitro Antitumor Assay (Assay 161)

The antiproliferative activity of various PRO polypeptides wasdetermined in the investigational, disease-oriented in vitro anti-cancerdrug discovery assay of the National Cancer Institute (NCI), using asulforhodamine B (SRB) dye binding assay essentially as described bySkehan et al., J. Natl. Cancer Inst. 82:1107-1112 (1990). The 60 tumorcell lines employed in this study (“the NCI panel”), as well asconditions for their maintenance and culture in vitro have beendescribed by Monks et al., J. Natl. Cancer Inst. 83:757-766 (1991). Thepurpose of this screen is to initially evaluate the cytotoxic and/orcytostatic activity of the test compounds against different types oftumors (Monks et al., supra; Boyd, Cancer: Princ. Pract. Oncol. Update3(10):1-12 [1989]).

Cells from approximately 60 human tumor cell lines were harvested withtrypsin/EDTA (Gibco), washed once, resuspended in IMEM and theirviability was determined. The cell suspensions were added by pipet (100μL volume) into separate 96-well microtiter plates. The cell density forthe 6-day incubation was less than for the 2-day incubation to preventovergrowth. Inoculates were allowed a preincubation period of 24 hoursat 37° C. for stabilization. Dilutions at twice the intended testconcentration were added at time zero in 100 μL aliquots to themicrotiter plate wells (1:2 dilution). Test compounds were evaluated atfive half-log dilutions (1000 to 100,000-fold). Incubations took placefor two days and six days in a 5% CO₂ atmosphere and 100% humidity.

After incubation, the medium was removed and the cells were fixed in 0.1ml of 10% trichloroacetic acid at 40° C. The plates were rinsed fivetimes with deionized water, dried, stained for 30 minutes with 0.1 ml of0.4% sulforhodamine B dye (Sigma) dissolved in 1% acetic acid, rinsedfour times with 1% acetic acid to remove unbound dye, dried, and thestain was extracted for five minutes with 0.1 ml of 10 mM Tris base[tris(hydroxymethyl)aminomethane], pH 10.5. The absorbance (OD) ofsulforhodamine B at 492 nm was measured using a computer-interfaced,96-well microtiter plate reader.

A test sample is considered positive if it shows at least 50% growthinhibitory effect at one or more concentrations. PRO polypeptidestesting positive in this assay are shown in Table 7, where theabbreviations are as follows:

NSCL=non-small cell lung carcinoma

CNS=central nervous system

TABLE 7 Test compound Tumor Cell Line Type Cell Line Designation PRO211NSCL HOP62 PRO211 Leukemia RPMI-8226 PRO211 Leukemia HL-60 (TB) PRO211NSCL NCI-H522 PRO211 CNS SF-539 PRO211 Melanoma LOX IMVI PRO211 BreastMDA-MB-435 PRO211 Leukemia MOLT-4 PRO211 CNS U251 PRO211 Breast MCF7PRO211 Leukemia HT-60 (TB) PRO211 Leukemia MOLT-4 PRO211 NSCL EKVXPRO211 NSCL NCI-H23 PRO211 NSCL NCI-H322M PRO211 NSCL NCI-H460 PRO211Colon HCT-116 PRO211 Colon HT29 PRO211 CNS SF-268 PRO211 CNS SF-295PRO211 CNS SNB-19 PRO211 CNS U251 PRO211 Melanoma LOX IMVI PRO211Melanoma SK-MEL-5 PRO211 Melanoma UACC-257 PRO211 Melanoma UACC-62PRO211 Ovarian OVCAR-8 PRO211 Renal RXF 393 PRO211 Breast MCF7 PRO211Breast NCI/ADR-REHS 578T PRO211 Breast T-47D PRO211 Leukemia HL-60 (TB)PRO211 Leukemia SR PRO211 NSCL NCI-H23 PRO211 Colon HCT-116 PRO211Melanoma LOX-IMVI PRO211 Melanoma SK-MEL-5 PRO211 Breast T-47D PRO228Leukemia MOLT-4 PRO228 NSCL EKVX PRO228 Colon KM12 PRO228 MelanomaUACC-62 PRO228 Ovarian OVCAR-3 PRO228 Renal TK10 PRO228 Renal SN12CPRO228 Breast MCF7 PRO228 Leukemia CCRF-CEM PRO228 Leukemia HL-60 (TB)PRO228 Colon COLO 205 PRO228 Colon HCT-15 PRO228 Colon KM12 PRO228 CNSSF-268 PRO228 CNS SNB-75 PRO228 Melanoma LOX-IMVI PRO228 MelanomaSK-MEL2 PRO228 Melanoma UACC-257 PRO228 Ovarian IGROV1 PRO228 OvarianOVCAR-4 PRO228 Ovarian OVCAR-5 PRO228 Ovarian OVCAR-8 PRO228 Renal 786-0PRO228 Renal CAKI-1 PRO228 Renal RXF 393 PRO228 Renal TK-10 PRO228 RenalUO-31 PRO228 Prostate PC-3 PRO228 Prostate DU-145 PRO228 Breast MCF7PRO228 Breast NCI/ADR-REHS 578T PRO228 Breast MDA-MB-435MDA-N PRO228Breast T-47D PRO219 Leukemia SR PRO219 NSCL NCI-H5222 PRO219 Breast MCF7PRO219 Leukemia K-562; RPMI-8226 PRO219 NSCL HOP-62; NCI-H322M PRO219NSCL NCI -H460 PRO219 Colon HT29; KM12; HCT-116 PRO219 CNS SF-539; U251PRO219 Prostate DU-145 PRO219 Breast MDA-N PRO219 Ovarian IGROV1 PRO219NSCL NCI-H226 PRO219 Leukemia MOLT-4 PRO219 NSCL A549/ATCC; EKVX;NCI-1123 PRO219 Colon HCC-2998 PRO219 CNS SF-295; SNB-19 PRO219 MelanomaSK-MEL-2; SK-MEL-5 PRO219 Melanoma UACC-257; UACC-62 PRO219 OvarianOCAR-4; SK-OV-3 PRO219 Renal 786-0; ACHN; CAKI-1; SN12C PRO219 RenalTK-10; UO-31 PRO219 Breast NCI/ADR-RES; BT-549; T-47D PRO219 BreastMDA-MB-435 PRO221 Leukemia CCRF-CEM PRO221 Leukemia MOLT-4 PRO221 NSCLHOP-62 PRO22I Breast MDA-N PRO221 Leukemia RPMI-8226; SR PRO221 NSCLNCI-H460 PRO221 Colon HCC-2998 PRO221 Ovarian IGROV1 PRO221 Renal TK-10PRO221 Breast MCF7 PRO221 Leukemia K-562 PRO221 Breast MDA-MB-435 PRO224Ovarian OVCAR-4 PRO224 Renal RXF 393 PRO224 Prostate DU-145 PRO224 NSCLHOP-62; NCI-H322M PRO224 Melanoma LOX IMVI PRO224 Ovarian OVCAR-8 PRO224Leukemia SR PRO224 NSCL NCI-H460 PRO224 CNS SF-295 PRO224 LeukemiaRPMI-8226 PRO224 Breast BT-549 PRO224 Leukemia CCRF-CEM; LH-60 (TB)PRO224 Colon HCT-116 PRO224 Breast MDA-MB-435 PRO224 Leukemia HL-60 (TB)PRO224 Colon HCC-2998 PRO224 Prostate PC-3 PRO224 CNS U251 PRO224 ColonHCT-15 PRO224 CNS SF-539 PRO224 Renal ACHN PRO328 Leukemia RPMI-8226PRO328 NSCL A549/ATCC; EKVX; HOP-62 PRO328 NSCL NCI-H23; NCI-H322MPRO328 Colon HCT-15; KM12 PRO328 CNS SF-295; SF-539; SNB-19; U251 PRO328Melanoma M14; UACC-257; UCAA-62 PRO328 Renal 786-0; ACHN PRO328 BreastMCF7 PRO328 Leukemia SR PRO328 Colon NCI-H23 PRO328 Melanoma SK-MEL-5PRO328 Prostate DU-145 PRO328 Melanoma LOX IMVI PRO328 Breast MDA-MB-435PRO328 Ovarian OVCAR-3 PRO328 Breast T-47D PRO301 NSCL NCI-H322M PRO301Leukemia MOLT-4; SR PRO301 NSCL A549/ATCC; EKVX; PRO301 NSCL NCI-H23;NCI-460; NCI-H226 PRO301 Colon COLO 205; HCC-2998; PRO301 Colon HCT-15;KM12; HT29; PRO301 Colon HCT-116 PRO301 CNS SF-268; SF-295; SNB-19PRO301 Melanoma MALME-3M; SK-MEL-2; PRO301 Melanoma SK-MEL-5;UACC-257PRO301 Melanoma UACC-62 PRO301 Ovarian IGROV1; OVCAR-4 PRO301 OvarianOVCAR-5 PRO301 Ovarian OVCAR-8; SK0OV-3 PRO301 Renal ACHN;CAKI-1; TK-10;UO-31 PRO301 Prostate PC-3; DU-145 PRO301 Breast NCI/ADR-RES; HS 578TPRO301 Breast MDA-MB-435;MDA-N; T-47D PRO301 Melanoma M14 PRO301Leukemia CCRF-CEM;HL-60(TB); K-562 PRO301 Leukemia RPMI-8226 PRO301Melanoma LOX IMVI PRO301 Renal 786-0; SN12C PRO301 Breast MCF7;MDA-MB-231/ATCC PRO301 Breast BT-549 PRO301 NSCL HOP-62 PRO301 CNSSF-539 PRO301 Ovarian OVCAR-3 PRO326 NSCL NCI-H322M PRO326 CNS SF295PRO326 CNS ST539 PRO326 CNS U251

The results of these assays demonstrate that the positive testing PROpolypeptides are useful for inhibiting neoplastic growth in a number ofdifferent tumor cell types and may be used therapeutically therefor.Antibodies against these PRO polypeptides are useful for affinitypurification of these useful polypeptides. Nucleic acids encoding thesePRO polypeptides are useful for the recombinant preparation of thesepolypeptides.

Example 92 Gene Amplification

This example shows that certain PRO polypeptide-encoding genes areamplified in the genome of certain human lung, colon and/or breastcancers and/or cell lines. Amplification is associated withoverexpression of the gene product, indicating that the polypeptides areuseful targets for therapeutic intervention in certain cancers such ascolon, lung, breast and other cancers and diagnostic determination ofthe presence of those cancers. Therapeutic agents may take the form ofantagonists of the PRO polypeptide, for example, murine-human chimeric,humanized or human antibodies against a PRO polypeptide.

The starting material for the screen was genomic DNA isolated from avariety cancers. The DNA is quantitated precisely, e.g.,fluorometrically. As a negative control, DNA was isolated from the cellsof ten normal healthy individuals which was pooled and used as assaycontrols for the gene copy in healthy individuals (not shown). The 5′nuclease assay (for example, TaqMan™) and real-time quantitative PCR(for example, ABI Prizm 7700 Sequence Detection System™ (Perkin Elmer,Applied Biosystems Division, Foster City, Calif.)), were used to findgenes potentially amplified in certain cancers. The results were used todetermine whether the DNA encoding the PRO polypeptide isover-represented in any of the primary lung or colon cancers or cancercell lines or breast cancer cell lines that were screened. The primarylung cancers were obtained from individuals with tumors of the type andstage as indicated in Table 8. An explanation of the abbreviations usedfor the designation of the primary tumors listed in Table 8 and theprimary tumors and cell lines referred to throughout this example aregiven below.

The results of the TaqMan™ are reported in delta (Δ) Ct units. One unitcorresponds to 1 PCR cycle or approximately a 2-fold amplificationrelative to normal, two units corresponds to 4-fold, 3 units to 8-foldamplification and so on. Quantitation was obtained using primers and aTaqMan™ fluorescent probe derived from the PRO polypeptide-encodinggene. Regions of the PRO polypeptide-encoding gene which are most likelyto contain unique nucleic acid sequences and which are least likely tohave spliced out introns are preferred for the primer and probederivation, e.g., 3′-untranslated regions. The sequences for the primersand probes (forward, reverse and probe) used for the PRO polypeptidegene amplification analysis were as follows:

PRO187 (DNA27864-1155) 27864.tm.p: 5′-GCAGATTTTGAGGACAGCCACCTCCA-3′ (SEQID NO:381) 27864.tm.f: 5′-GGCCTTGCAGACAACCGT-3′ (SEQ ID NO:382)27864.tm.r: 5′-CAGACTGAGGGAGATCCGAGA-3′ (SEQ ID NO:383) 27864.tm.p2:5′-CAGCTGCCCTTCCCCAACCA-3′ (SEQ ID NO:384) 27864.tm.f2:5′-CATCAAGCGCCTCTACCA-3′ (SEQ ID NO:385) 27864.tm.r2:5′-CACAAACTCGAACTGCTTCTG-3′ (SEQ ID NO:386) PRO214 (DNA32286-1191):32286.3utr-5: 5′-GGGCCATCACAGCTCCCT-3′ (SEQ ID NO:387) 32286.3utr-3b:5′-GGGATGTGGTGAACACAGAACA-3′ (SEQ ID NO:388) 32286.3utr-probe:5′-TGCCAGCTGCATGCTGCCAGTT-3′ (SEQ ID NO:389) PRO211 (DNA32292-1131):32292.3utr-5: 5′-CAGAAGGATGTCCCGTGGAA-3′ (SEQ ID NO:390) 32292.3utr-3:5′-GCCGCTGTCCACTGCAG-3′ (SEQ ID NO:391) 32292.3utr-probe.rc:5′-GACGGCATCCTCAGGGCCACA-3′ (SEQ ID NO:392) PRO230 (DNA33223-1136):33223.tm.p3: 5′-ATGTCCTCCATGCCCACGCG-3′ (SEQ ID NO:393) 33223.tm.f3:5′-GAGTGCGACATCGAGAGCTT-3′ (SEQ ID NO:394) 33223.tm.r3:5′-CCGCAGCCTCAGTGATGA-3′ (SEQ ID NO:395) 33223.3utr-5:5′-GAAGAGCACAGCTGCAGATCC-3′ (SEQ ID NO:396) 33223.3utr-3:5′-GAGGTGTCCTGGCTTTGGTAGT-3′ (SEQ ID NO:397) 33223.3utr-probe:5′-CCTCTGGCGCCCCCACTCAA-3′ (SEQ ID NO:398) PRO317 (DNA33461-1199):33461.tm.f: 5′-CCAGGAGAGCTGGCGATG-3′ (SEQ ID NO:399) 33461.tm.r:5′-GCAAATTCAGGGCTCACTAGAGA-3′ (SEQ ID NO:400) 33461.tm.p:5′-CACAGAGCATTTGTCCATCAGCAGTT (SEQ ID NO:401) CAG-3′ PRO246(DNA35639-1172): 35639.3utr-5: 5′-GGCAGAGACTTCCAGTCACTGA-3′ (SEQ IDNO:402) 35639.3utr-3: 5′-GCCAAGGGTGGTGTTAGATAGG-3′ (SEQ ID NO:403)35639.3utr-probe: 5′-CAGGCCCCCTTGATCTGTACCCCA-3′ (SEQ ID NO:404) PRO533(DNA49435-1219): 49435.tm.f: 5′-GGGACGTGCTTCTACAAGAACAG-3′ (SEQ IDNO:405) 49435.tm.r: 5′-CAGGCTTACAATGTTATGATCAGACA-3′ (SEQ ID NO:406)49435.tm.p: 5′-TATTCAGAGTTTTCCATTGGCAGTGCC (SEQ ID NO:407) AGTT-3′PRO343 (DNA43318-1217): 43318.tm.f1 5′-TCTACATCAGCCTCTCTGCGC-3′ (SEQ IDNO:408) 43318.tm.p1 5′-CGATCTTCTCCACCCAGGAGCGG-3′ (SEQ ID NO:409)43318.tm.r1 5′-GGAGCTGCACCCCTTGC-3′ (SEQ ID NO:237) PRO232(DNA34435-1140): 34435.3utr-5: 5′-GCCAGGCCTCACATTCGT-3′ (SEQ ID NO:410)DNA34435.3utr-probe: 5′-CTCCCTGAATGGCAGCCTGAGCA-3′ (SEQ ID NO:411)DNA34435.3utr-3: 5′-AGGTGTTTATTAAGGGCCTACGCT-3′ (SEQ ID NO:412) PRO269(DNA38260-1180): 38260.tm.f: 5′-CAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:413)3826O.tm.p: 5′-TGGCGGAGTCCCCTCTTGGCT-3′ (SEQ ID NO:414) 38260.tm.r:5′-CCCTGTTTCCCTATGCATCACT-3′ (SEQ ID NO:415) PRO304 (DNA39520-1217):39520.tm.f: 5′-TCAACCCCTGACCCTTTCCTA-3′ (SEQ ID NO:416) 39520.tm.p:5′-GGCAGGGGACAAGCCATCTCTCCT-3′ (SEQ ID NO:417) 39520.tm.r:5′-GGGACTGAACTGCCAGCTTC-3′ (SEQ ID NO:418) PRO339 (DNA43466-1225):43466.tm.f1: 5′-GGGCCCTAACCTCATTACCTTT-3′ (SEQ ID NO:419) 43466.tm.p1:5′-TGTCTGCCTCAGCCCCAGGAAGG-3′ (SEQ ID NO:420) 43466.tm.r1:5′-TCTGTCCACCATCTTGCCTTG-3′ (SEQ ID NO:421)

The 5′ nuclease assay reaction is a fluorescent PCR-based techniquewhich makes use of the 5′ exonuclease activity of Taq DNA polymeraseenzyme to monitor amplification in real time. Two oligonucleotideprimers (forward [.f] and reverse [.r]) are used to generate an amplicontypical of a PCR reaction. A third oligonucleotide, or probe (.p), isdesigned to detect nucleotide sequence located between the two PCRprimers. The probe is non-extendible by Taq DNA polymerase enzyme, andis labeled with a reporter fluorescent dye and a quencher fluorescentdye. Any laser-induced emission from the reporter dye is quenched by thequenching dye when the two dyes are located close together as they areon the probe. During the amplification reaction, the Taq DNA polymeraseenzyme cleaves the probe in a template-dependent manner. The resultantprobe fragments disassociate in solution, and signal from the releasedreporter dye is free from the quenching effect of the secondfluorophore. One molecule of reporter dye is liberated for each newmolecule synthesized, and detection of the unquenched reporter dyeprovides the basis for quantitative interpretation of the data.

The 5′ nuclease procedure is run on a real-time quantitative PCR devicesuch as the ABI Prism 7700TM Sequence Detection. The system consists ofa thermocycler, laser, charge-coupled device (CCD) camera and computer.The system amplifies samples in a 96-well format on a thermocycler.During amplification, laser-induced fluorescent signal is collected inreal-time through fiber optics cables for all 96 wells, and detected atthe CCD. The system includes software for running the instrument and foranalyzing the data.

5′ Nuclease assay data are initially expressed as Ct, or the thresholdcycle. This is defined as the cycle at which the reporter signalaccumulates above the background level of fluorescence. The ΔCt valuesare used as quantitative measurement of the relative number of startingcopies of a particular target sequence in a nucleic acid sample whencomparing cancer DNA results to normal human DNA results.

Table 8 describes the stage, T stage and N stage of various primarytumors which were used to screen the PRO polypeptide compounds of theinvention.

TABLE 8 Primary Lung and Colon Tumor Profiles Primary Tumor Stage StageOther Stage Dukes Stage T Stage N Stage Human lung tumor AdenoCa(SRCC724) [LT1] IIA T1 N1 Human lung tumor SqCCa (SRCC725) [LT1a] IIB T3N0 Human lung tumor AdenoCa (SRCC726) [LT2] IB T2 N0 Human lung tumorAdenoCa (SRCC727) [LT3] IIIA T1 N2 Human lung tumor AdenoCa (SRCC728)[LT4] IB T2 N0 Human lung tumor SqCCa (SRCC729) [LT6] IB T2 N0 Humanlung tumor Aden/SqCCa (SRCC730) [LT7] IA T1 N0 Human lung tumor AdenoCa(SRCC731) [LT9] IB T2 N0 Human lung tumor SqCCa (SRCC732) [LT10] IIB T2N1 Human lung tumor SqCCa (SRCC733) [LT11] IIA T1 N1 Human lung tumorAdenoCa (SRCC734) [LT12] IV T2 N0 Human lung tumor AdenoSqCCa(SRCC735)[LT13] IB T2 N0 Human lung tumor SqCCa (SRCC736) [LT15] IB T2N0 Human lung tumor SqCCa (SRCC737) [LT16] IB T2 N0 Human lung tumorSqCCa (SRCC738) [LT17] IIB T2 N1 Human lung tumor SqCCa (SRCC739) [LT18]IB T2 N0 Human lung tumor SqCCa (SRCC740) [LT19] IB T2 N0 Human lungtumor LCCa (SRCC741) [LT21] IIB T3 N1 Human lung AdenoCa (SRCC811)[LT22] IA T1 N0 Human colon AdenoCa (SRCC742) [CT2] M1 D pT4 N0 Humancolon AdenoCa (SRCC743) [CT3] B pT3 N0 Human colon AdenoCa (SRCC744)[CT8] B T3 N0 Human colon AdenoCa (SRCC745) [CT10] A pT2 N0 Human colonAdenoCa (SRCC746) [CT12] MO, R1 B T3 N0 Human colon AdenoCa (SRCC747)[CT14] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC748) [CT15] M1, R2 DT4 N2 Human colon AdenoCa (SRCC749) [CT16] pMO B pT3 pN0 Human colonAdenoCa (SRCC750) [CT17] C1 pT3 pN1 Human colon AdenoCa (SRCC751) [CT1]MO, R1 B pT3 N0 Human colon AdenoCa (SRCC752) [CT4] B pT3 M0 Human colonAdenoCa (SRCC753) [CT5] G2 C1 pT3 pN0 Human colon AdenoCa (SRCC754)[CT6] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC755) [CT7] G1 A pT2 pN0Human colon AdenoCa (SRCC756) [CT9] G3 D pT4 pN2 Human colon AdenoCa(SRCC757) [CT11] B T3 N0 Human colon AdenoCa (SRCC758) [CT18] MO, RO BpT3 pN0

DNA Preparation

DNA was prepared from cultured cell lines, primary tumors, normal humanblood. The isolation was performed using purification kit, buffer setand protease and all from Quiagen, according to the manufacturer'sinstructions and the description below.

Cell Culture Lysis

Cells were washed and trypsinized at a concentration of 7.5×10⁸ per tipand pelleted by centrifuging at 1000 rpm for 5 minutes at 4° C.,followed by washing again with ½ volume of PBS recentrifugation. Thepellets were washed a third time, the suspended cells collected andwashed 2× with PBS. The cells were then suspended into 10 ml PBS. BufferC1 was equilibrated at 4° C. Qiagen protease #19155 was diluted into6.25 ml cold ddH₂O to a final concentration of 20 mg/ml and equilibratedat 4° C. 10 ml of G2 Buffer w by diluting Qiagen RNAse A stock (100mg/ml) to a final concentration of 200 μg/ml.

Buffer C1 (10 ml, 4° C.) and ddH2O (40 ml, 4° C.) were then added to the10 ml of cell suspension, mixed by inverting and incubated on ice for 10minutes. The cell nuclei were pelleted by centrifuging in a Beckmanswinging bucket rotor at 2500 rpm at 4° C. for 15 minutes. Thesupernatant was discarded and the nuclei were suspended with a vortexinto 2 ml Buffer C1 (at 4° C.) and 6 ml ddH₂O, followed by a second 4°C. centrifugation at 2500 rpm for 15 minutes. The nuclei were thenresuspended into the residual buffer using 200 μl per tip. G2 buffer (10ml) was added to the suspended nuclei while gentle vortexing wasapplied. Upon completion of buffer addition, vigorous vortexing wasapplied for 30 seconds. Quiagen protease (200 μl, prepared as indicatedabove) was added and incubated at 50° C. for 60 minutes. The incubationand centrifugation was repeated until the lysates were clear (e.g.,incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4°C.)

Solid Human Tumor Sample Preparation and Lysis

Tumor samples were weighed and placed into 50 ml conical tubes and heldon ice. Processing was limited to no more than 250 mg tissue perpreparation (1 tip/preparation). The protease solution was freshlyprepared by diluting into 6.25 ml cold ddH₂O to a final concentration of20 mg/ml and stored at 4° C. G2 buffer (20 ml) was prepared by dilutingDNAse A to a final concentration of 200 mg/ml (from 100 mg/ml stock).The tumor tissue was homogenated in 19 ml G2 buffer for 60 seconds usingthe large tip of the polytron in a laminar-flow TC hood in order toavoid inhalation of aerosols, and held at room temperature. Betweensamples, the polytron was cleaned by spinning at 2×30 seconds each in 2LddH₂O, followed by G2 buffer (50 ml). If tissue was still present on thegenerator tip, the apparatus was disassembled and cleaned.

Quiagen protease (prepared as indicated above, 1.0 ml) was added,followed by vortexing and incubation at 50° C. for 3 hours. Theincubation and centrifugation was repeated until the lysates were clear(e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10min., 4° C.).

Human Blood Preparation and Lysis

Blood was drawn from healthy volunteers using standard infectious agentprotocols and citrated into 10 ml samples per tip. Quiagen protease wasfreshly prepared by dilution into 6.25 ml cold ddH₂O to a finalconcentration of 20 mg/ml and stored at 4° C. G2 buffer was prepared bydiluting RNAse A to a final concentration of 200 μg/ml from 100 mg/mlstock. The blood (10 ml) was placed into a 50 ml conical tube and 10 mlC1 buffer and 30 ml ddH₂O (both previously equilibrated to 4° C.) wereadded, and the components mixed by inverting and held on ice for 10minutes. The nuclei were pelleted with a Beckman swinging bucket rotorat 2500 rpm, 4° C. for 15 minutes and the supernatant discarded. With avortex, the nuclei were suspended into 2 ml C1 buffer (4° C.) and 6 mlddH₂O (4° C.). Vortexing was repeated until the pellet was white. Thenuclei were then suspended into the residual buffer using a 200 μl tip.G2 buffer (10 ml) were added to the suspended nuclei while gentlyvortexing, followed by vigorous vortexing for 30 seconds. Quiagenprotease was added (200 μl) and incubated at 50° C. for 60 minutes. Theincubation and centrifugation was repeated until the lysates were clear(e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10min., 4° C.).

Purification of Cleared Lysates

(1) Isolation of Genomic DNA:

Genomic DNA was equilibrated (I sample per maxi tip preparation) with 10ml QBT buffer. QF elution buffer was equilibrated at 50° C. The sampleswere vortexed for 30 seconds, then loaded onto equilibrated tips anddrained by gravity. The tips were washed with 2×15 ml QC buffer. The DNAwas eluted into 30 ml silanized, autoclaved 30 ml Corex tubes with 15 mlQF buffer (50° C.). Isopropanol (10.5 ml) was added to each sample, thetubes covered with parafin and mixed by repeated inversion until the DNAprecipitated. Samples were pelleted by centrifugation in the SS-34 rotorat 15,000 rpm for 10 minutes at 4° C. The pellet location was marked,the supernatant discarded, and 10 ml 70% ethanol (4° C.) was added.Samples were pelleted again by centrifugation on the SS-34 rotor at10,000 rpm for 10 minutes at 4° C. The pellet location was marked andthe supernatant discarded. The tubes were then placed on their side in adrying rack and dried 10 minutes at 37° C., taking care not to overdrythe samples.

After drying, the pellets were dissolved into 1.0 ml TE (pH 8.5) andplaced at 50° C. for 1-2 hours. Samples were held overnight at 4° C. asdissolution continued. The DNA solution was then transferred to 1.5 mltubes with a 26 gauge needle on a tuberculin syringe. The transfer wasrepeated 5× in order to shear the DNA. Samples were then placed at 50°C. for 1-2 hours.

(2) Quantitation of Genomic DNA and Preparation for Gene AmplificationAssay

The DNA levels in each tube were quantified by standard A₂₆₀, A₂₈₀spectrophotometry on a 1:20 dilution (5 μl DNA+95 μl ddH₂O) using the0.1 ml quartz cuvetts in the Beckman DU640 spectrophotometer. A₂₆₀/A₂₈₀ratios were in the range of 1.8-1.9. Each DNA samples was then dilutedfurther to approximately 200 ng/ml in TE (pH 8.5). If the originalmaterial was highly concentrated (about 700 ng/μl), the material wasplaced at 50° C. for several hours until resuspended.

Fluorometric DNA quantitation was then performed on the diluted material(20-600 ng/ml) using the manufacturer's guidelines as modified below.This was accomplished by allowing a Hoeffer DyNA Quant 200 fluorometerto warm-up for about 15 minutes. The Hoechst dye working solution(#H33258, 10 μl prepared within 12 hours of use) was diluted into 100 ml1×TNE buffer. A 2 ml cuvette was filled with the fluorometer solution,placed into the machine, and the machine was zeroed. pGEM 3Zf(+) (2 μl,lot #360851026) was added to 2 ml of fluorometer solution and calibratedat 200 units. An additional 2 μl of pGEM 3Zf(+) DNA was then tested andthe reading confirmed at 400 +/−10 units. Each sample was then read atleast in triplicate. When 3 samples were found to be within 10% of eachother, their average was taken and this value was used as thequantification value.

The fluorometricly determined concentration was then used to dilute eachsample to 10 ng/μl in ddH₂O. This was done simultaneously on alltemplate samples for a single TaqMan plate assay, and with enoughmaterial to run 500-1000 assays. The samples were tested in triplicatewith Taqman™ primers and probe both B-actin and GAPDH on a single platewith normal human DNA and no-template controls. The diluted samples wereused provided that the CT value of normal human DNA subtracted from testDNA was +/−1 Ct. The diluted, lot-qualified genomic DNA was stored in1.0 ml aliquots at −80° C. Aliquots which were subsequently to be usedin the gene amplification assay were stored at 4° C. Each 1 ml aliquotis enough for 8-9 plates or 64 tests

Gene Amplification Assay

The PRO polypeptide compounds of the invention were screened in thefollowing primary tumors and the resulting ΔCt values greater than orequal to 1.0 are reported in Table 9 below.

TABLE 9 ΔCt values in lung and colon primary tumors and cell line modelsPrimary Tumors or Cell PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO-PRO- PRO- lines 187 533 214 343 211 230 246 317 232 269 304 339 LT7 1.521.04 1.08 LT13 2.74 1.85 2.71 1.88 3.42 1.63 1.90 1.27 1.29 1.04 2.981.83 2.23 2.26 3.22 1.68 2.24 2.44 2.84 2.93 2.15 2.75 2.53 1.82 LT31.57 1.97 1.06 1.86 1.17 LT4 1.17 1.18 LT9 1.42 1.04 1.80 1.03 LT12 2.701.38 2.23 1.51 2.86 1.54 2.54 2.40 1.14 1.15 1.26 2.90 1.49 1.50 1.272.96 2.47 1.74 2.27 2.92 1.25 2.68 2.28 1.34 LT30 1.67 2.13 1.36 LT211.26 1.09 1.50 LT1-a 1.02 1.18 1.29 LT6 1.93 LT10 1.96 1.07 2.57 LT111.09 1.67 1.00 2.05 1.32 3.43 2.20 1.14 1.51 1.39 1.80 1.89 1.14 1.412.33 1.54 1.02 LT15 3.75 1.77 3.62 2.44 4.32 2.11 2.06 1.86 1.36 1.343.92 1.58 1.30 2.16 4.47 1.56 2.76 3.49 3.64 1.63 2.94 3.56 3.32 2.68LT16 2.10 1.66 1.70 1.25 1.15 1.55 1.00 2.04 1.08 1.83 1.33 LT17 1.321.93 1.15 1.85 1.26 2.68 2.29 1.35 1.42 1.68 1.63 1.87 2.30 1.39 1.692.03 1.30 1.10 1.33 1.30 LT18 1.17 1.04 LT19 4.05 1.67 2.09 3.82 2.424.05 1.91 2.51 1.21 1.60 1.15 3.99 1.98 2.55 4.92 1.68 2.03 4.93 1.163.78 4.76 HF-000840 1.58 Calu-1 1.08 SW900 1.86 CT2 3.56 2.49 1.95 1.422.75 3.49 2.36 CT3 2.06 1.15 1.34 CT8 1.01 1.48 1.29 1.58 CT10 1.81 1.841.88 1.00 1.88 1.49 1.55 CT12 1.81 1.74 1.13 CT14 1.82 2.48 2.33 1.361.72 1.24 CT15 1.63 2.06 1.33 1.41 1.04 CT16 1.95 1.78 1.40 CT17 2.042.40 1.74 CT1 1.24 1.22 1.27 1.25 2.41 1.34 1.46 1.14 CT4 1.36 1.77 1.331.32 1.10 1.17 2.05 1.42 1.02 CT5 2.96 1.56 2.68 1.76 2.27 1.33 1.592.99 2.76 1.64 2.39 CT6 1.10 1.33 1.01 1.14 CT7 1.40 1.66 1.39 1.00 CT91.39 1.16 1.09 1.24 1.13 CT11 2.22 2.05 1.55 2.01 1.75 1.48 1.92 2.261.85 1.83 1.12 HF000539 1.57 SW620 1.14 HF000611 4.64 HF000733 1.93 2.33HF000716 1.68 2.82 CT18 1.29

Summary

Because amplification of the various DNA's as described above occurs invarious tumors, it is likely associated with tumor formation and/orgrowth. As a result, antagonists (e.g., antibodies) directed againstthese polypeptides would be expected to be useful in cancer therapy.

Example 94 Detection of PRO Polypeptides That Affect Glucose or FFAUptake by Primary Rat Adipocytes (Assay 94)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by adipocyte cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by adipocytes would bebeneficial including, for example, obesity, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat adipocytes, and allowed to incubate overnight. Samples are taken at4 and 16 hours and assayed for glycerol, glucose and FFA uptake. Afterthe 16 hour incubation, insulin is added to the media and allowed toincubate for 4 hours. At this time, a sample is taken and glycerol,glucose and FFA uptake is measured. Media containing insulin without thePRO polypeptide is used as a positive reference control. As the PROpolypeptide being tested may either stimulate or inhibit glucose and FFAuptake, results are scored as positive in the assay if greater than 1.5times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as stimulators of glucoseand/or FFA uptake in this assay: PRO221, PRO235, PRO245, PRO295, PRO301and PRO332.

The following PRO polypeptides tested positive as inhibitors of glucoseand/or FFA uptake in this assay: PRO214, PRO219, PRO228, PRO222, PRO231and PRO265.

Example 95 Chondrocyte Re-differentiation Assay (Assay 110)

This assay shows that certain polypeptides of the invention act toinduce redifferentiation of chondrocytes, therefore, are expected to beuseful for the treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis. The assay is performedas follows. Porcine chondrocytes are isolated by overnight collagenasedigestion of articulary cartilage of metacarpophalangeal joints of 4-6month old female pigs. The isolated cells are then seeded at 25,000cells/cm² in Ham F-12 containing 10% FBS and 4 μg/ml gentamycin. Theculture media is changed every third day and the cells are then seededin 96 well plates at 5,000 cells/well in 100 μl of the same mediawithout serum and 100 μl of the test PRO polypeptide, 5 nM staurosporin(positive control) or medium alone (negative control) is added to give afinal volume of 200 μl/well. After 5 days of incubation at 37° C., apicture of each well is taken and the differentiation state of thechondrocytes is determined. A positive result in the assay occurs whenthe redifferentiation of the chondrocytes is determined to be moresimilar to the positive control than the negative control.

The following polypeptide tested positive in this assay: PRO214, PRO219,PRO229, PRO222, PRO224, PRO230, PRO257, PRO272 and PRO301.

Example 96 Fetal Hemoglobin Induction in an Erythroblastic Cell Line(Assay 107)

This assay is useful for screening PRO polypeptides for the ability toinduce the switch from adult hemoglobin to fetal hemoglobin in anerythroblastic cell line. Molecules testing positive in this assay areexpected to be useful for therapeutically treating various mammalianhemoglobin-associated disorders such as the various thalassemias. Theassay is performed as follows. Erythroblastic cells are plated instandard growth medium at 1000 cells/well in a 96 well format. PROpolypeptides are added to the growth medium at a concentration of 0.2%or 2% and the cells are incubated for 5 days at 37° C. As a positivecontrol, cells are treated with 100 μM hemin and as a negative control,the cells are untreated. After 5 days, cell lysates are prepared andanalyzed for the expression of gamma globin (a fetal marker). A positivein the assay is a gamma globin level at least 2-fold above the negativecontrol.

The following polypeptides tested positive in this assay: PRO221 andPRO245.

Example 97 Mouse Kidney Mesangial Cell Proliferation Assay (Assay 92)

This assay shows that certain polypeptides of the invention act toinduce proliferation of mammalian kidney mesangial cells and, therefore,are useful for treating kidney disorders associated with decreasedmesangial cell function such as Berger disease or other nephropathiesassociated with Schönlein-Henoch purpura, celiac disease, dermatitisherpetiformis or Crohn disease. The assay is performed as follows. Onday one, mouse kidney mesangial cells are plated on a 96 well plate ingrowth media (3:1 mixture of Dulbecco's modified Eagle's medium andHam's F12 medium, 95% fetal bovine serum, 5% supplemented with 14 mMHEPES) and grown overnight. On day 2, PRO polypeptides are diluted at 2concentrations(1% and 0.1%) in serum-free medium and added to the cells.Control samples are serum-free medium alone. On day 4, 20 μl of the CellTiter 96 Aqueous one solution reagent (Progema) was added to each welland the colormetric reaction was allowed to proceed for 2 hours. Theabsorbance (OD) is then measured at 490 nm. A positive in the assay isanything that gives an absorbance reading which is at least 15% abovethe control reading.

The following polypeptide tested positive in this assay: PRO227.

Example 98 Proliferation of Rat Utricular Supporting Cells (Assay 54)

This assay shows that certain polypeptides of the invention act aspotent mitogens for inner ear supporting cells which are auditory haircell progenitors and, therefore, are useful for inducing theregeneration of auditory hair cells and treating hearing loss inmammals. The assay is performed as follows. Rat UEC-4 utricularepithelial cells are aliquoted into 96 well plates with a density of3000 cells/well in 200 μl of serum-containing medium at 33° C. The cellsare cultured overnight and are then switched to serum-free medium at 37°C. Various dilutions of PRO polypeptides (or nothing for a control) arethen added to the cultures and the cells are incubated for 24 hours.After the 24 hour incubation, ³H-thymidine (1 μCi/well) is added and thecells are then cultured for an additional 24 hours. The cultures arethen washed to remove unincorporated radiolabel, the cells harvested andCpm per well determined. Cpm of at least 30% or greater in the PROpolypeptide treated cultures as compared to the control cultures isconsidered a positive in the assay.

The following polypeptides tested positive in this assay: PRO310 andPRO346.

Example 99 Chondrocyte Proliferation Assay (Assay 111)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce the proliferation and/orredifferentiation of chondrocytes in culture. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis.

Porcine chondrocytes are isolated by overnight collagenase digestion ofarticular cartilage of the metacarpophalangeal joint of 4-6 month oldfemale pigs. The isolated cells are then seeded at 25,000 cells/cm² inHam F-12 containing 10% FBS and 4 μg/ml gentamycin. The culture media ischanged every third day and the cells are reseeded to 25,000 cells/cm²every five days. On day 12, the cells are seeded in 96 well plates at5,000 cells/well in 100 μl of the same media without serum and 100 μl ofeither serum-free medium (negative control), staurosporin (finalconcentration of 5 nM; positive control) or the test PRO polypeptide areadded to give a final volume of 200 μl/well. After 5 days at 37° C., 20μl of Alamar blue is added to each well and the plates are incubated foran additional 3 hours at 37° C. The fluorescence is then measured ineach well (Ex:530 nm; Em: 590 nm). The fluorescence of a platecontaining 200 μl of the serum-free medium is measured to obtain thebackground. A positive result in the assay is obtained when thefluorescence of the PRO polypeptide treated sample is more like that ofthe positive control than the negative control.

The following PRO polypeptides tested positive in this assay: PRO219,PRO222, PRO317, PRO257, PRO265, PRO287, PRO272 and PRO533.

Example 100 Inhibition of Heart Neonatal Hypertrophy Induced by LIF+ET-1(Assay 74)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to inhibit neonatal heart hypertrophyinduced by LIF and endothelin-1 (ET-1). A test compound that provides apositive response in the present assay would be useful for thetherapeutic treatment of cardiac insufficiency diseases or disorderscharacterized or associated with an undesired hypertrophy of the cardiacmuscle.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats (180 μl at7.5×10⁴/ml, serum <0.1, freshly isolated) are introduced on day 1 to96-well plates previously coated with DMEM/F12+4% FCS. Test PROpolypeptide samples or growth medium alone (negative control) are thenadded directly to the wells on day 2 in 20 μl volume. LIF+ET-1 are thenadded to the wells on day 3. The cells are stained after an additional 2days in culture and are then scored visually the next day. A positive inthe assay occurs when the PRO polypeptide treated myocytes are visuallysmaller on the average or less numerous than the untreated myocytes.

The following PRO polypeptides tested positive in this assay: PRO238.

Example 101 Tissue Expression Distribution

Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3′ end of its associatedtemplate in a standard PCR reaction. The oligonucleotide probes wereemployed in standard quantitative PCR amplification reactions with cDNAlibraries isolated from different human adult and/or fetal tissuesources and analyzed by agarose gel electrophoresis so as to obtain aquantitative determination of the level of expression of the PROpolypeptide-encoding nucleic acid in the various tissues tested.Knowledge of the expression pattern or the differential expression ofthe PRO polypeptide-encoding nucleic acid in various different humantissue types provides a diagnostic marker useful for tissue typing, withor without other tissue-specific markers, for determining the primarytissue source of a metastatic tumor, and the like. These assays providedthe following results.

Tissues With Tissues Lacking DNA Molecule Significant ExpressionSignificant Expression DNA34436-1238 lung, placenta, brain testisDNA35557-1137 lung, kidney, brain placenta DNA35599-1168 kidney, brainliver, placenta DNA35668-1171 liver, lung, kidney placenta, brainDNA36992-1168 liver, lung, kidney, brain placenta DNA39423-1182 kidney,brain liver DNA40603-1232 liver brain, kidney, lung DNA40604-1187 liverbrain, kidney, lung DNA41379-1236 lung, brain liver DNA33206-1165 heart,spleen, dendro- substantia nigra, cytes hippocampus, cartilage,prostate, HUVEC DNA34431-1177 spleen, HUVEC, brain, colon tumor,cartilage, heart, uterus prostate, THP-1 macrophages DNA41225-1217HUVEC, uterus, spleen, brain, colon tumor, heart, IM-9 cartilage,prostate lymphoblasts

Example 102 In situ Hybridization

In situ hybridization is a powerful and versatile technique for thedetection and localization of nucleic acid sequences within cell ortissue preparations. It may be useful, for example, to identify sites ofgene expression, analyze the tissue distribution of transcription,identify and localize viral infection, follow changes in specific mRNAsynthesis and aid in chromosome mapping.

In situ hybridization was performed following an optimized version ofthe protocol by Lu and Gillett, Cell Vision 1:169-176 (1994), usingPCR-generated ³³P-labeled riboprobes. Briefly, formalin-fixed,paraffin-embedded human tissues were sectioned, deparaffinized,deproteinated in proteinase K (20 g/ml) for 15 minutes at 37° C., andfurther processed for in situ hybridization as described by Lu andGillett, supra. A [³³-P] UTP-labeled antisense riboprobe was generatedfrom a PCR product and hybridized at 55° C. overnight. The slides weredipped in Kodak NTB2 nuclear track emulsion and exposed for 4 weeks.

³³P-Riboprobe Synthesis

6.0 μl (125 mCi) of ³³P-UTP (AmershamBF 1002, SA<2000 Ci/mmol) werespeed vac dried. To each tube containing dried ³³P-UTP, the followingingredients were added:

2.0 μl 5×transcription buffer

1.0 μl DTT (100 mM)

2.0 μl NTP mix (2.5 mM: 10μ; each of 10 mM GTP, CTP & ATP+10 μl H₂O)

1.0 μl UTP (50 μM)

1.0 μl Rnasin

1.0 μl DNA template (1 μg)

1.0 μl H₂O

1.0 μl RNA polymerase (for PCR products T3=AS, T7=S, usually)

The tubes were incubated at 37° C. for one hour. 1.0 μl RQ1 DNase wereadded, followed by incubation at 37° C. for 15 minutes. 90 μl TE (10 mMTris pH 7.6/1 mM EDTA pH 8.0) were added, and the mixture was pipettedonto DE81 paper. The remaining solution was loaded in a Microcon-50ultrafiltration unit, and spun using program 10 (6 minutes). Thefiltration unit was inverted over a second tube and spun using program 2(3 minutes). After the final recovery spin, 100 μl TE were added. 1 μlof the final product was pipetted on DE81 paper and counted in 6 ml ofBiofluor II.

The probe was run on a TBE/urea gel. 1-3 μl of the probe or 5 μl of RNAMrk III were added to 3 μl of loading buffer. After heating on a 95° C.heat block for three minutes, the gel was immediately placed on ice. Thewells of gel were flushed, the sample loaded, and run at 180-250 voltsfor 45 minutes. The gel was wrapped in saran wrap and exposed to XARfilm with an intensifying screen in −70° C. freezer one hour toovernight.

³³P-Hybridization

A. Pretreatment of Frozen Sections

The slides were removed from the freezer, placed on aluminium trays andthawed at room temperature for 5 minutes. The trays were placed in 55°C. incubator for five minutes to reduce condensation. The slides werefixed for 10 minutes in 4% paraformaldehyde on ice in the fume hood, andwashed in 0.5×SSC for 5 minutes, at room temperature (25 ml 20'SSC+975ml SQ H₂O). After deproteination in 0.5 μg/ml proteinase K for 10minutes at 37° C. (12.5 μl of 10 mg/ml stock in 250 ml prewarmedRNase-free RNAse buffer), the sections were washed in 0.5×SSC for 10minutes at room temperature. The sections were dehydrated in 70%, 95%,100% ethanol, 2 minutes each.

B. Pretreatment of Paraffin-embedded Sections

The slides were deparaffinized, placed in SQ H₂O, and rinsed twice in2×SSC at room temperature, for 5 minutes each time. The sections weredeproteinated in 20 μg/ml proteinase K (500 μl of 10 mg/ml in 250 mlRNase-free RNase buffer; 37° C., 15 minutes)—human embryo, or8×proteinase K (100 μl in 250 ml Rnase buffer, 37° C., 30minutes)—formalin tissues. Subsequent rinsing in 0.5×SSC and dehydrationwere performed as described above.

C. Prehybridization

The slides were laid out in a plastic box lined with Box buffer (4×SSC,50% formamide)—saturated filter paper. The tissue was covered with 50 μlof hybridization buffer (3.75 g Dextran Sulfate+6 ml SQ H₂O), vortexedand heated in the microwave for 2 minutes with the cap loosened. Aftercooling on ice, 18.75 ml formamide, 3.75 ml 20×SSC and 9 ml SQ H₂O wereadded, the tissue was vortexed well, and incubated at 42° C. for 1-4hours.

D. Hybridization

1.0×10⁶ cpm probe and 1.0 μl tRNA (50 mg/ml stock) per slide were heatedat 95° C. for 3 minutes The slides were cooled on ice, and 48 μlhybridization buffer were added per slide. After vortexing, 50 μl ³³Pmix were added to 50 μl prehybridization on slide. The slides wereincubated overnight at 55° C.

E. Washes

Washing was done 2×10 minutes with 2×SSC, EDTA at room temperature (400ml 20×SSC+16 ml 0.25M EDTA, V_(f)=4L), followed by RNaseA treatment at37° C. for 30 minutes (500 μl of 10 mg/ml in 250 ml Rnase buffer=20μg/ml), The slides were washed 2×10 minutes with 2 ×SSC, EDTA at roomtemperature. The stringency wash conditions were as follows: 2 hours at55° C., 0.1×SSC, EDTA (20 ml 20×SSC+16 ml EDTA, V_(f)=4L).

F. Oligonucleotides

In situ analysis was performed on a variety of DNA sequences disclosedherein. The oligonucleotides employed for these analyses are as follows.

(1) DNA33094-11131 (PRO217) p15′-GGATTCTAATACGACTCACTATAGGGCTCAGAAAAGCGCAACAGAGAA-3′ (SEQ ID NO:348)p2 5′-CTATGAAATTAACCCTCACTAAAGGGATGTCTTCCATGCCAACCTTC-3′ (SEQ ID NO:349)(2) DNA33223-1136 (PRO230) p15′-GGATTCTAATACGACTCACTATAGGGCGGCGATGTCCACTGGGGCTAC-3′ (SEQ ID NO:350)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACGAGGAAGATGGGCGGATGGT-3′ (SEQ IDNO:351) (3) DNA34435-1140 (PRO232) p15′-GGATTCTAATACGACTCACTATAGGGCACCCACGCGTCCGGCTGCTT-3′ (SEQ ID NO:352) p25′-CTATGAAATTAACCCTCACTAAAGGGACGGGGGACACCACGGACCAGA-3′ (SEQ ID NO:353)(4) DNA35639-1172 (PRO246) p15′-GGATTCTAATACGACTCACTATAGGGCTTGCTGCGGTTTTTGTTCCTG-3′ (SEQ ID NO:354)p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGCTGCCGATCCCACTGGTATT-3′ (SEQ IDNO:355) (5) DNA49435-1219 (PRO533) p15′-GGATTCTAATACGACTCACTATAGGGCGGATCCTGGCCGGCCTCTG-3′ (SEQ ID NO:356) p25′-CTATGAAATTAACCCTCACTAAAGGGAGCCCGGGCATGGTCTCAGTTA-3′ (SEQ ID NO:357)(6) DNA35638-1141 (PRO245) p15′-GGATTCTAATACGACTCACTATAGGGCGGGAAGATGGCGAGGAGGAG-3′ (SEQ ID NO:358) p25′-CTATGAAATTAACCCTCACTAAAGGGACCAAGGCCACAAACGGAAATC-3′ (SEQ ID NO:359)(7) DNA33089-1132 (PRO221) p15′-GGATTCTAATACGACTCACTATAGGGCTGTGCTTTCATTCTGCCAGTA-3′ (SEQ ID NO:360)p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGGGTACAATTAAGGGGTGGAT-3′ (SEQ IDNO:361) (8) DNA35918-1174 (PRO258) p15′-GGATTCTAATACGACTCACTATAGGGCCCGCCTCGCTCCTGCTCCTG-3′ (SEQ ID NO:362) p25′-CTATGAAATTAACCCTCACTAAAGGGAGGATTGCCGCGACCCTCACAG-3′ (SEQ ID NO:363)(9) DNA32286-1191 (PRO214) p15′-GGATTCTAATACGACTCACTATAGGGCCCCTCCTGCCTTCCCTGTCC-3′ (SEQ ID NO:364) p25′-CTATGAAATTAACCCTCACTAAAGGGAGTGGTGGCCGCGATTATCTGC-3′ (SEQ ID NO:365)(10) DNA33221-1133 (PRO224) p15′-GGATTCTAATACGACTCACTATAGGGCGCAGCGATGGCAGCGATGAGG-3′ (SEQ ID NO:366)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACAGACGGGGCAGAGGGAGTG-3′ (SEQ ID NO:367)(11) DNA35557-1137 (PRO234) p15′-GGATTCTAATACGACTCACTATAGGGCCAGGAGGCGTGAGGAGAAAC-3′ (SEQ ID NO:368) p25′-CTATGAAATTAACCCTCACTAAAGGGAAAGACATGTCATCGGGAGTGG-3′ (SEQ ID NO:369)(12) DNA33100-1159 (PRO229) p15′-GGATTCTAATACGACTCACTATAGGGCCGGGTGGAGGTGGAACAGAAA-3′ (SEQ ID NO:370)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACACAGACAGAGCCCCATACGC-3′ (SEQ ID NO371) (13) DNA34431-1177 (PRO263) p15′-GGATTCTAATACGACTCACTATAGGGCCAGGGAAATCCGGATGTCTC-3′ (SEQ ID NO:372) p25′-CTATGAAATTAACCCTCACTAAAGGGAGTAAGGGGATGCCACCGAGTA-3′ (SEQ ID NO:373)(14) DNA38268-1188 (PRO295) p15′-GGATTCTAATACGACTCACTATAGGGCCAGCTACCCGCAGGAGGAGG-3′ (SEQ ID NO:374) p25′-CTATGAAATTAACCCTCACTAAAGGGATCCCAGGTGATGAGGTCCAGA-3′ (SEQ ID NO:375)

G. Results

In situ analysis was performed on a variety of DNA sequences disclosedherein. The results from these analyses are as follows.

(1) DNA33094-1131 (PRO217)

Highly distinctive expression pattern, that does not indicate an obviousbiological function. In the human embryo it was expressed in outersmooth muscle layer of the GI tract, respiratiry cartilage, branchingrespiratory epithelium, osteoblasts, tendons, gonad, in the optic nervehead and developing dermis. In the adult expression was observed in theepidermal pegs of the chimp tongue, the basal epithelial/myoepithelialcells of the prostate and urinary bladder. Also expressed in thealveolar lining cells of the adult lung, mesenchymal cells juxtaposed toerectile tissue in the penis and the cerebral cortex (probably glialcells). In the kidney, expression was only seen in disease, in cellssurrounding thyroidized renal tubules.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung,skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic,acute failure).

Non-human primate tissues examined:

(a) Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

(b) Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum,penis.

(2) DNA33223-1136 (PRO230)

Sections show an intense signal associated with arterial and venousvessels in the fetus. In arteries the signal appeared to be confined tosmooth-muscle/pericytic cells. The signal is also seen in capillaryvessels and in glomeruli. It is not clear whether or not endothelialcells are expressing this mRNA. Expression is also observed inepithelial cells in the fetal lens. Strong expression was also seen incells within placental trophoblastic villi, these cells lie between thetrophoblast and the fibroblast-like cells that express HGF—uncertainhistogenesis. In the adult, there was no evidence of expression and thewall of the aorta and most vessels appear to be negative. However,expression was seen over vascular channels in the normal prostate and inthe epithelium lining the gallbladder. Insurers expression was seen inthe vessels of the soft-tissue sarcoma and a renal cell carcinoma. Insummary, this is a molecule that shows relatively specific vascularexpression in the fetus as well as in some adult organs. Expression wasalso observed in the fetal lens and the adult gallbladder.

In a secondary screen, vascular expression was observed, similar to thatobserved above, seen in fetal blocks. Expression is on vascular smoothmuscle, rather than endothelium. Expression also seen in smooth muscleof the developing oesophagus, so as reported previously, this moleculeis not vascular specific. Expression was examined in 4 lung and 4 breastcarcinomas. Substantial expression was seen in vascular smooth muscle ofat least ¾ lung cancers and {fraction (2/4)} breast cancers. Inaddition, in one breast carcinoma, expression was observed inperitumoral stromal cells of uncertain histogenesis (possiblymyofibroblasts). No endothelial cell expression was observed in thisstudy.

(3) DNA34435-1140 (PRO232)

Strong expression in prostatic epithelium and bladder epithelium, lowerlevel of expression in bronchial epithelium. High background/low levelexpression seen in a number of sites, including among others, bone,blood, chondrosarcoma, adult heart and fetal liver. It is felt that thislevel of signal represents background, partly because signal at thislevel was seen over the blood. All other tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

In a secondary screen, expression was observed in the epithelium of theprostate, the superficial layers of the urethelium of the urinarybladder, the urethelium lining the renal pelvis and the urethelium ofthe ureter (1 out of 2 experiments). The urethra of a rhesus monkey wasnegative; it is unclear whether this represents a true lack ofexpression by the urethra, or if it is the result of a failure of theprobe to cross react with rhesus tissue. The findings in the prostateand bladder are similar to those previously described using an isotopicdetection technique. Expression of the mRNA for this antigen is NOTprostate epithelial specific. The antigen may serve as a useful markerfor urethelial derived tissues. Expression in the superficial,post-mitotic cells, of the urinary tract epithelium also suggest that itis unlikely to represent a specific stem cell marker, as this would beexpected to be expressed specifically in basal epithelium.

(4) DNA35639-1172 (PRO246)

Strongly expressed in fetal vascular endothelium, including tissues ofthe CNS. Lower level of expression in adult vasculature, including theCNS. Not obviously expressed at higher levels in tumor vascularendothelium. Signal also seen over bone matrix and adult spleen, notobviously cell associated, probably related to non-specific backgroundat these sites.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

(5) DNA49435-1219 (PRO533)

Moderate expression over cortical neurones in the fetal brain.Expression over the inner aspect of the fetal retina, possibleexpression in the developing lens. Expression over fetal skin,cartilage, small intestine, placental villi and umbilical cord. In adulttissues there is an extremely high level of expression over thegallbladder epithelium. Moderate expression over the adult kidney,gastric and colonic epithelia. Low-level expression was observed overmany cell types in many tissues, this may be related to stickiness ofthe probe, these data should therefore be interpreted with a degree ofcaution.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

(6) DNA35638-1141 (PRO245)

Expression observed in the endothelium lining a subset of fetal andplacental vessels. Endothelial expression was confined to these tissueblocks. Expression also observed over intermediate trophoblast cells ofplacenta. Expression also observed tumor vasculature but not in thevasculature of normal tissues of the same type. All other tissuesnegative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma, thyroid (chimp), parathyroid(chimp) ovary (chimp) and chondrosarcoma. Acetominophen induced liverinjury and hepatic cirrhosis

(7) DNA33089-1132 (PRO221)

Specific expression over fetal cerebral white and grey matter, as wellas over neurones in the spinal cord. Probe appears to cross react withrat. Low level of expression over cerebellar neurones in adult rhesusbrain. All other tissues negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis

(8) DNA35918-1174 (PRO258)

Strong expression in the nervous system. In the rhesus monkey brainexpression is observed in cortical, hippocampal and cerebellar neurones.Expression over spinal neurones in the fetal spinal cord, the developingbrain and the inner aspects of the fetal retina. Expression overdeveloping dorsal root and autonomic ganglia as well as enteric nerves.Expression observed over ganglion cells in the adult prostate. In therat, there is strong expression over the developing hind brain andspinal cord. Strong expression over interstitial cells in the placentalvilli. All other tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, renal cell carcinoma, adrenal,aorta, spleen, lymph node, pancreas, lung, myocardium, skin, cerebralcortex (rm), hippocampus(rm), cerebellum(rm), bladder, prostate,stomach, gastric carcinoma, colon, colonic carcinoma, thyroid (chimp),parathyroid (chimp) ovary (chimp) and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis.

(9) DNA32286-1191 (PRO214)

Fetal tissue: Low level throughout mesenchyme. Moderate expression inplacental stromal cells in membranous tissues and in thyroid. Low levelexpression in cortical neurones. Adult tissue: all negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined include: Liver, kidney, adrenal, myocardium,aorta, spleen, lymph node, pancreas, lung and skin.

(10) DNA33221-1133 (PRO224)

Expression limited to vascular endothelium in fetal spleen, adultspleen, fetal liver, adult thyroid and adult lymph node (chimp).Additional site of expression is the developing spinal ganglia. Allother tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, pancreas, lung, skin, eye (inc.retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(11) DNA35557-1137 (PRO234)

Specific expression over developing motor neurones in ventral aspect ofthe fetal spinal cord (will develop into ventral horns of spinal cord).All other tissues negative. Possible role in growth, differentiationand/or development of spinal motor neurons.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis

(12) DNA33100-1159 (PRO229)

Striking expression in mononuclear phagocytes (macrophages) of fetal andadult spleen, liver, lymph node and adult thymus (in tingible bodymacrophages). The highest expression is in the spleen. All other tissuesnegative. Localisation and homology are entirely consistent with a roleas a scavenger receptor for cells of the reticuloendothelial system.Expression also observed in placental mononuclear cells.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung,skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic,acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(13) DNA34431-1177 (PRO263)

Widepread expression in human fetal tissues and placenta overmononuclear cells, probably macrophages +/− lymphocytes. The cellulardistribution follows a perivascular pattern in many tissues. Strongexpression also seen in epithelial cells of the fetal adrenal cortex.All adult tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, spleen, lymph node,pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), bladder, stomach, colon and colonic carcinoma.Acetominophen induced liver injury and hepatic cirrhosis.

A secondary screen evidenced expression over stromal mononuclear cellsprobably histiocytes.

(14) DNA38268-1188 (PRO295)

High expression over ganglion cells in human fetal spinal ganglia andover large neurones in the anterior horns of the developing spinal cord.In the adult there is expression in the chimp adrenal medulla (neural),neurones of the rhesus monkey brain (hippocampus [+++] and cerebralcortex) and neurones in ganglia in the normal adult human prostate (theonly section that contains ganglion cells, i.e. expression in this celltype is presumed NOT to be confined to the prostate). All other tissuesnegative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, great vessels,stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinalcord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

Example 103 Isolation of cDNA Clones Encoding Human PRO1868

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA49803. Based up an observed homology between theDNA49803 consensus sequence and an EST sequence contained within theIncyte EST clone no. 2994689, Incyte EST clone no. 2994689 was purchasedand its insert obtained and sequenced. The sequence of that insert isshown in FIG. 123 and is herein designated DNA77624-2515.

The entire nucleotide sequence of DNA77624-2515 is shown in FIG. 123(SEQ ID NO:422). Clone DNA77624-2515 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 51-53 and ending at the stop codon at nucleotide positions981-983 (FIG. 123). The predicted polypeptide precursor is 310 aminoacids long (FIG. 124). The full-length PRO1868 protein shown in FIG. 124has an estimated molecular weight of about 35,020 daltons and a pI ofabout 7.90. Analysis of the full-length PRO1868 sequence shown in FIG.124 (SEQ ID NO:423) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 30, a transmembranedomain from about amino acid 243 to about amino acid 263, potentialN-glycosylation sites from about amino acid 104 to about amino acid 107and from about amino acid 192 to about amino acid 195, a cAMP- andcGMP-dependent protein kinase phosphorylation site from about amino acid107 to about amino acid 110, casein kinase II phosphorylation sites fromabout amino acid 106 to about amino acid 109 and from about amino acid296 to about amino acid 299, a tyrosine kinase phosphorylation site fromabout amino acid 69 to about amino acid 77 and potential N-myristolationsites from about amino acid 26 to about amino acid 31, from about aminoacid 215 to about amino acid 220, from about amino acid 226 to aboutamino acid 231, from about amino acid 243 to about amino acid 248, fromabout amino acid 244 to about amino acid 249 and from about amino acid262 to about amino acid 267. Clone DNA77624-2515 has been deposited withATCC on Dec. 22, 1998 and is assigned ATCC deposit no. 203553.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 124 (SEQ ID NO:423), evidenced significant homologybetween the PRO1868 amino acid sequence and the following Dayhoffsequences: HGS_RC75, P_W61379, A33_HUMAN, P_W14146, P_W14158,AMAL_DROME, P_R77437, I38346, NCM2_HUMAN and PTPD_HUMAN.

Example 104 Identification of Receptor/Ligand Interactions

In this assay, various PRO polypeptides are tested for ability to bindto a panel of potential receptor molecules for the purpose ofidentifying receptor/ligand interactions. The identification of a ligandfor a known receptor, a receptor for a known ligand or a novelreceptor/ligand pair is useful for a variety of indications including,for example, targeting bioactive molecules (linked to the ligand orreceptor) to a cell known to express the receptor or ligand, use of thereceptor or ligand as a reagent to detect the presence of the ligand orreceptor in a composition suspected of containing the same, wherein thecomposition may comprise cells suspected of expressing the ligand orreceptor, modulating the growth of or another biological orimmunological activity of a cell known to express or respond to thereceptor or ligand, modulating the immune response of cells or towardcells that express the receptor or ligand, allowing the preparation ofagonists, antagonists and/or antibodies directed against the receptor orligand which will modulate the growth of or a biological orimmunological activity of a cell expressing the receptor or ligand, andvarious other indications which will be readily apparent to theordinarily skilled artisan.

The assay is performed as follows. A PRO polypeptide of the presentinvention suspected of being a ligand for a receptor is expressed as afusion protein containing the Fc domain of human IgG (an immunoadhesin).Receptor-ligand binding is detected by allowing interaction of theimmunoadhesin polypeptide with cells (e.g. Cos cells) expressingcandidate PRO polypeptide receptors and visualization of boundimmunoadhesin with fluorescent reagents directed toward the Fc fusiondomain and examination by microscope. Cells expressing candidatereceptors are produced by transient transfection, in parallel, ofdefined subsets of a library of cDNA expression vectors encoding PROpolypeptides that may function as receptor molecules. Cells are thenincubated for 1 hour in the presence of the PRO polypeptideimmunoadhesin being tested for possible receptor binding. The cells arethen washed and fixed with paraformaldehyde. The cells are thenincubated with fluorescent conjugated antibody directed against the Fcportion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goatanti-human-Fc antibody). The cells are then washed again and examined bymicroscope. A positive interaction is judged by the presence offluorescent labeling of cells transfected with cDNA encoding aparticular PRO polypeptide receptor or pool of receptors and an absenceof similar fluorescent labeling of similarly prepared cells that havebeen transfected with other cDNA or pools of cDNA. If a defined pool ofcDNA expression vectors is judged to be positive for interaction with aPRO polypeptide immunoadhesin, the individual cDNA species that comprisethe pool are tested individually (the pool is “broken down ”) todetermine the specific cDNA that encodes a receptor able to interactwith the PRO polypeptide immunoadhesin.

In another embodiment of this assay, an epitope-tagged potential ligandPRO polypeptide (e.g. 8 histidine “His ” tag) is allowed to interactwith a panel of potential receptor PRO polypeptide molecules that havebeen expressed as fusions with the Fc domain of human IgG(immunoadhesins). Following a 1 hour co-incubation with the epitopetagged PRO polypeptide, the candidate receptors are eachimmunoprecipitated with protein A beads and the beads are washed.Potential ligand interaction is determined by western blot analysis ofthe immunoprecipitated complexes with antibody directed towards theepitope tag. An interaction is judged to occur if a band of theanticipated molecular weight of the epitope tagged protein is observedin the western blot analysis with a candidate receptor, but is notobserved to occur with the other members of the panel of potentialreceptors.

Using these assays, the following receptor/ligand interactions have beenherein identified: PRO245 binds to PRO1868.

DEPOSIT OF MATERIAL

The following materials have been deposited with the American TypeCulture Collection, 10801 University Boulevard, Manassas, Va. USA(ATCC):

Material ATCC Dep. No. Deposit Date DNA32292-1131 ATCC 209258 Sep. 16,1997 DNA33094-1131 ATCC 209256 Sep. 16, 1997 DNA33223-1136 ATCC 209264Sep. 16, 1997 DNA34435-1140 ATCC 209250 Sep. 16, 1997 DNA27864-1155 ATCC209375 Oct. 16, 1997 DNA36350-1158 ATCC 209378 Oct. 16, 1997DNA32290-1164 ATCC 209384 Oct. 16, 1997 DNA35639-1172 ATCC 209396 Oct.17, 1997 DNA33092-1202 ATCC 209420 Oct. 28, 1997 DNA49435-1219 ATCC209480 Nov. 21, 1997 DNA35638-1141 ATCC 209265 Sep. 16, 1997DNA32298-1132 ATCC 209257 Sep. 16, 1997 DNA33089-1132 ATCC 209262 Sep.16, 1997 DNA33786-1132 ATCC 209253 Sep. 16, 1997 DNA35918-1174 ATCC209402 Oct. 17, 1997 DNA37150-1178 ATCC 209401 Oct. 17, 1997DNA38260-1180 ATCC 209397 Oct. 17, 1997 DNA39969-1185 ATCC 209400 Oct.17, 1997 DNA32286-1191 ATCC 209385 Oct. 16, 1997 DNA33461-1199 ATCC209367 Oct. 15, 1997 DNA40628-1216 ATCC 209432 Nov. 7, 1997DNA33221-1133 ATCC 209263 Sep. 16, 1997 DNA33107-1135 ATCC 209251 Sep.16, 1997 DNA35557-1137 ATCC 209255 Sep. 16, 1997 DNA34434-1139 ATCC209252 Sep. 16, 1997 DNA33100-1159 ATCC 209373 Oct. 16, 1997DNA35600-1162 ATCC 209370 Oct. 16, 1997 DNA34436-1238 ATCC 209523 Dec.10, 1997 DNA33206-1165 ATCC 209372 Oct. 16, 1997 DNA35558-1167 ATCC209374 Oct. 16, 1997 DNA35599-1168 ATCC 209373 Oct. 16, 1997DNA36992-1168 ATCC 209382 Oct. 16, 1997 DNA34407-1169 ATCC 209383 Oct.16, 1997 DNA35841-1173 ATCC 209403 Oct. 17, 1997 DNA33470-1175 ATCC209398 Oct. 17, 1997 DNA34431-1177 ATCC 209399 Oct. 17, 1997DNA39510-1181 ATCC 209392 Oct. 17, 1997 DNA39423-1182 ATCC 209387 Oct.17, 1997 DNA40620-1183 ATCC 209388 Oct. 17, 1997 DNA40604-1187 ATCC209394 Oct. 17, 1997 DNA38268-1188 ATCC 209421 Oct. 28, 1997DNA37151-1193 ATCC 209393 Oct. 17, 1997 DNA35673-1201 ATCC 209418 Oct.28, 1997 DNA40370-1217 ATCC 209485 Nov. 21, 1997 DNA42551-1217 ATCC209483 Nov. 21, 1997 DNA39520-1217 ATCC 209482 Nov. 21, 1997DNA41225-1217 ATCC 209491 Nov. 21, 1997 DNA43318-1217 ATCC 209481 Nov.21, 1997 DNA40587-1231 ATCC 209438 Nov. 7, 1997 DNA41338-1234 ATCC209927 Jun. 2, 1998 DNA40981-1234 ATCC 209439 Nov. 7, 1997 DNA37140-1234ATCC 209489 Nov. 21, 1997 DNA40982-1235 ATCC 209433 Nov. 7, 1997DNA41379-1236 ATCC 209488 Nov. 21, 1997 DNA44167-1243 ATCC 209434 Nov.7, 1997 DNA39427-1179 ATCC 209395 Oct. 17, 1997 DNA40603-1232 ATCC209486 Nov. 21, 1997 DNA43466-1225 ATCC 209490 Nov. 21, 1997DNA43046-1225 ATCC 209484 Nov. 21, 1997 DNA35668-1171 ATCC 209371 Oct.16, 1997 DNA77624-2515 ATCC 203553 Dec. 22, 1998

These deposit were made under the provisions of the Budapest Treaty onthe International Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure and the Regulations there under (BudapestTreaty). This assures maintenance of a viable culture of the deposit for30 years from the date of deposit. The deposits will be made availableby ATCC under the terms of the Budapest Treaty, and subject to anagreement between Genentech, Inc. and ATCC, which assures that allrestrictions imposed by the depositor on the availability to the publicof the deposited material will be irrevocably removed upon the grantingof the pertinent U.S. patent, assures permanent and unrestrictedavailability of the progeny of the culture of the deposit to the publicupon issuance of the pertinent U.S. patent or upon laying open to thepublic of any U.S. or foreign patent application, whichever comes first,and assures availability of the progeny to one determined by the U.S.Commissioner of Patents and Trademarks to be entitled thereto accordingto 35 USC § 122 and the Commissioner's rules pursuant thereto (including37 CFR § 1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture ofthe materials on deposit should die or be lost or destroyed whencultivated under suitable conditions, the materials will be promptlyreplaced on notification with another of the same. Availability of thedeposited material is not to be construed as a license to practice theinvention in contravention of the rights granted under the authority ofany government in accordance with its patent laws.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by the construct deposited,since the deposited embodiment is intended as a single illustration ofcertain aspects of the invention and any constructs that arefunctionally equivalent are within the scope of this invention. Thedeposit of material herein does not constitute an admission that thewritten description herein contained is inadequate to enable thepractice of any aspect of the invention, including the best modethereof, nor is it to be construed as limiting the scope of the claimsto the specific illustrations that it represents. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and fall within the scope of the appended claims.

                   #             SEQUENCE LISTING<160> NUMBER OF SEQ ID NOS: 423 <210> SEQ ID NO 1 <211> LENGTH: 1825<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1actgcacctc ggttctatcg attgaattcc ccggggatcc tctagagatc cc#tcgacctc     60gacccacgcg tccgggccgg agcagcacgg ccgcaggacc tggagctccg gc#tgcgtctt    120cccgcagcgc tacccgccat gcgcctgccg cgccgggccg cgctggggct cc#tgccgctt    180ctgctgctgc tgccgcccgc gccggaggcc gccaagaagc cgacgccctg cc#accggtgc    240cgggggctgg tggacaagtt taaccagggg atggtggaca ccgcaaagaa ga#actttggc    300ggcgggaaca cggcttggga ggaaaagacg ctgtccaagt acgagtccag cg#agattcgc    360ctgctggaga tcctggaggg gctgtgcgag agcagcgact tcgaatgcaa tc#agatgcta    420gaggcgcagg aggagcacct ggaggcctgg tggctgcagc tgaagagcga at#atcctgac    480ttattcgagt ggttttgtgt gaagacactg aaagtgtgct gctctccagg aa#cctacggt    540cccgactgtc tcgcatgcca gggcggatcc cagaggccct gcagcgggaa tg#gccactgc    600agcggagatg ggagcagaca gggcgacggg tcctgccggt gccacatggg gt#accagggc    660ccgctgtgca ctgactgcat ggacggctac ttcagctcgc tccggaacga ga#cccacagc    720atctgcacag cctgtgacga gtcctgcaag acgtgctcgg gcctgaccaa ca#gagactgc    780ggcgagtgtg aagtgggctg ggtgctggac gagggcgcct gtgtggatgt gg#acgagtgt    840gcggccgagc cgcctccctg cagcgctgcg cagttctgta agaacgccaa cg#gctcctac    900acgtgcgaag agtgtgactc cagctgtgtg ggctgcacag gggaaggccc ag#gaaactgt    960aaagagtgta tctctggcta cgcgagggag cacggacagt gtgcagatgt gg#acgagtgc   1020tcactagcag aaaaaacctg tgtgaggaaa aacgaaaact gctacaatac tc#cagggagc   1080tacgtctgtg tgtgtcctga cggcttcgaa gaaacggaag atgcctgtgt gc#cgccggca   1140gaggctgaag ccacagaagg agaaagcccg acacagctgc cctcccgcga ag#acctgtaa   1200tgtgccggac ttacccttta aattattcag aaggatgtcc cgtggaaaat gt#ggccctga   1260ggatgccgtc tcctgcagtg gacagcggcg gggagaggct gcctgctctc ta#acggttga   1320ttctcatttg tcccttaaac agctgcattt cttggttgtt cttaaacaga ct#tgtatatt   1380ttgatacagt tctttgtaat aaaattgacc attgtaggta atcaggagga aa#aaaaaaaa   1440aaaaaaaaaa aaagggcggc cgcgactcta gagtcgacct gcagaagctt gg#ccgccatg   1500gcccaacttg tttattgcag cttataatgg ttacaaataa agcaatagca tc#acaaattt   1560cacaaataaa gcattttttt cactgcattc tagttgtggt ttgtccaaac tc#atcaatgt   1620atcttatcat gtctggatcg ggaattaatt cggcgcagca ccatggcctg aa#ataacctc   1680tgaaagagga acttggttag gtaccttctg aggcggaaag aaccagctgt gg#aatgtgtg   1740tcagttaggg tgtggaaagt ccccaggctc cccagcaggc agaagtatgc aa#gcatgcat   1800 ctcaattagt cagcaaccca gtttt          #                   #             1825 <210> SEQ ID NO 2<211> LENGTH: 353 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 2 Met Arg Leu Pro Arg Arg Ala Ala Leu Gly Le#u Leu Pro Leu Leu Leu   1               5  #                 10 #                 15 Leu Leu Pro Pro Ala Pro Glu Ala Ala Lys Ly#s Pro Thr Pro Cys His              20      #             25     #             30 Arg Cys Arg Gly Leu Val Asp Lys Phe Asn Gl#n Gly Met Val Asp Thr          35          #         40         #         45 Ala Lys Lys Asn Phe Gly Gly Gly Asn Thr Al#a Trp Glu Glu Lys Thr      50              #     55             #     60 Leu Ser Lys Tyr Glu Ser Ser Glu Ile Arg Le#u Leu Glu Ile Leu Glu  65                  # 70                 # 75                  # 80 Gly Leu Cys Glu Ser Ser Asp Phe Glu Cys As#n Gln Met Leu Glu Ala                  85  #                 90 #                 95 Gln Glu Glu His Leu Glu Ala Trp Trp Leu Gl#n Leu Lys Ser Glu Tyr             100       #           105      #           110 Pro Asp Leu Phe Glu Trp Phe Cys Val Lys Th#r Leu Lys Val Cys Cys         115           #       120          #       125 Ser Pro Gly Thr Tyr Gly Pro Asp Cys Leu Al#a Cys Gln Gly Gly Ser     130               #   135              #   140 Gln Arg Pro Cys Ser Gly Asn Gly His Cys Se#r Gly Asp Gly Ser Arg 145                 1 #50                 1#55                 1 #60 Gln Gly Asp Gly Ser Cys Arg Cys His Met Gl#y Tyr Gln Gly Pro Leu                 165   #               170  #               175 Cys Thr Asp Cys Met Asp Gly Tyr Phe Ser Se#r Leu Arg Asn Glu Thr             180       #           185      #           190 His Ser Ile Cys Thr Ala Cys Asp Glu Ser Cy#s Lys Thr Cys Ser Gly         195           #       200          #       205 Leu Thr Asn Arg Asp Cys Gly Glu Cys Glu Va#l Gly Trp Val Leu Asp     210               #   215              #   220 Glu Gly Ala Cys Val Asp Val Asp Glu Cys Al#a Ala Glu Pro Pro Pro 225                 2 #30                 2#35                 2 #40 Cys Ser Ala Ala Gln Phe Cys Lys Asn Ala As#n Gly Ser Tyr Thr Cys                 245   #               250  #               255 Glu Glu Cys Asp Ser Ser Cys Val Gly Cys Th#r Gly Glu Gly Pro Gly             260       #           265      #           270 Asn Cys Lys Glu Cys Ile Ser Gly Tyr Ala Ar#g Glu His Gly Gln Cys         275           #       280          #       285 Ala Asp Val Asp Glu Cys Ser Leu Ala Glu Ly#s Thr Cys Val Arg Lys     290               #   295              #   300 Asn Glu Asn Cys Tyr Asn Thr Pro Gly Ser Ty#r Val Cys Val Cys Pro 305                 3 #10                 3#15                 3 #20 Asp Gly Phe Glu Glu Thr Glu Asp Ala Cys Va#l Pro Pro Ala Glu Ala                 325   #               330  #               335 Glu Ala Thr Glu Gly Glu Ser Pro Thr Gln Le#u Pro Ser Arg Glu Asp             340       #           345      #           350 Leu <210> SEQ ID NO 3 <211> LENGTH: 2206 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 3caggtccaac tgcacctcgg ttctatcgat tgaattcccc ggggatcctc ta#gagatccc     60tcgacctcga cccacgcgtc cgccaggccg ggaggcgacg cgcccagccg tc#taaacggg    120aacagccctg gctgagggag ctgcagcgca gcagagtatc tgacggcgcc ag#gttgcgta    180ggtgcggcac gaggagtttt cccggcagcg aggaggtcct gagcagcatg gc#ccggagga    240gcgccttccc tgccgccgcg ctctggctct ggagcatcct cctgtgcctg ct#ggcactgc    300gggcggaggc cgggccgccg caggaggaga gcctgtacct atggatcgat gc#tcaccagg    360caagagtact cataggattt gaagaagata tcctgattgt ttcagagggg aa#aatggcac    420cttttacaca tgatttcaga aaagcgcaac agagaatgcc agctattcct gt#caatatcc    480attccatgaa ttttacctgg caagctgcag ggcaggcaga atacttctat ga#attcctgt    540ccttgcgctc cctggataaa ggcatcatgg cagatccaac cgtcaatgtc cc#tctgctgg    600gaacagtgcc tcacaaggca tcagttgttc aagttggttt cccatgtctt gg#aaaacagg    660atggggtggc agcatttgaa gtggatgtga ttgttatgaa ttctgaaggc aa#caccattc    720tccaaacacc tcaaaatgct atcttcttta aaacatgtca acaagctgag tg#cccaggcg    780ggtgccgaaa tggaggcttt tgtaatgaaa gacgcatctg cgagtgtcct ga#tgggttcc    840acggacctca ctgtgagaaa gccctttgta ccccacgatg tatgaatggt gg#actttgtg    900tgactcctgg tttctgcatc tgcccacctg gattctatgg agtgaactgt ga#caaagcaa    960actgctcaac cacctgcttt aatggaggga cctgtttcta ccctggaaaa tg#tatttgcc   1020ctccaggact agagggagag cagtgtgaaa tcagcaaatg cccacaaccc tg#tcgaaatg   1080gaggtaaatg cattggtaaa agcaaatgta agtgttccaa aggttaccag gg#agacctct   1140gttcaaagcc tgtctgcgag cctggctgtg gtgcacatgg aacctgccat ga#acccaaca   1200aatgccaatg tcaagaaggt tggcatggaa gacactgcaa taaaaggtac ga#agccagcc   1260tcatacatgc cctgaggcca gcaggcgccc agctcaggca gcacacgcct tc#acttaaaa   1320aggccgagga gcggcgggat ccacctgaat ccaattacat ctggtgaact cc#gacatctg   1380aaacgtttta agttacacca agttcatagc ctttgttaac ctttcatgtg tt#gaatgttc   1440aaataatgtt cattacactt aagaatactg gcctgaattt tattagcttc at#tataaatc   1500actgagctga tatttactct tccttttaag ttttctaagt acgtctgtag ca#tgatggta   1560tagattttct tgtttcagtg ctttgggaca gattttatat tatgtcaatt ga#tcaggtta   1620aaattttcag tgtgtagttg gcagatattt tcaaaattac aatgcattta tg#gtgtctgg   1680gggcagggga acatcagaaa ggttaaattg ggcaaaaatg cgtaagtcac aa#gaatttgg   1740atggtgcagt taatgttgaa gttacagcat ttcagatttt attgtcagat at#ttagatgt   1800ttgttacatt tttaaaaatt gctcttaatt tttaaactct caatacaata ta#ttttgacc   1860ttaccattat tccagagatt cagtattaaa aaaaaaaaaa ttacactgtg gt#agtggcat   1920ttaaacaata taatatattc taaacacaat gaaataggga atataatgta tg#aacttttt   1980gcattggctt gaagcaatat aatatattgt aaacaaaaca cagctcttac ct#aataaaca   2040ttttatactg tttgtatgta taaaataaag gtgctgcttt agttttttgg aa#aaaaaaaa   2100aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa gggcggccgc gactctagag tc#gacctgca   2160 gaagcttggc cgccatggcc caacttgttt attgcagctt ataatg   #               2206 <210> SEQ ID NO 4 <211> LENGTH: 379 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 4Met Ala Arg Arg Ser Ala Phe Pro Ala Ala Al #a Leu Trp Leu Trp Ser  1               5  #                 10  #                 15Ile Leu Leu Cys Leu Leu Ala Leu Arg Ala Gl #u Ala Gly Pro Pro Gln             20      #             25      #             30Glu Glu Ser Leu Tyr Leu Trp Ile Asp Ala Hi #s Gln Ala Arg Val Leu         35          #         40          #         45Ile Gly Phe Glu Glu Asp Ile Leu Ile Val Se #r Glu Gly Lys Met Ala     50              #     55              #     60Pro Phe Thr His Asp Phe Arg Lys Ala Gln Gl #n Arg Met Pro Ala Ile 65                  # 70                  # 75                  # 80Pro Val Asn Ile His Ser Met Asn Phe Thr Tr #p Gln Ala Ala Gly Gln                 85  #                 90  #                 95Ala Glu Tyr Phe Tyr Glu Phe Leu Ser Leu Ar #g Ser Leu Asp Lys Gly            100       #           105       #           110Ile Met Ala Asp Pro Thr Val Asn Val Pro Le #u Leu Gly Thr Val Pro        115           #       120           #       125His Lys Ala Ser Val Val Gln Val Gly Phe Pr #o Cys Leu Gly Lys Gln    130               #   135               #   140Asp Gly Val Ala Ala Phe Glu Val Asp Val Il #e Val Met Asn Ser Glu145                 1 #50                 1 #55                 1 #60Gly Asn Thr Ile Leu Gln Thr Pro Gln Asn Al #a Ile Phe Phe Lys Thr                165   #               170   #               175Cys Gln Gln Ala Glu Cys Pro Gly Gly Cys Ar #g Asn Gly Gly Phe Cys            180       #           185       #           190Asn Glu Arg Arg Ile Cys Glu Cys Pro Asp Gl #y Phe His Gly Pro His        195           #       200           #       205Cys Glu Lys Ala Leu Cys Thr Pro Arg Cys Me #t Asn Gly Gly Leu Cys    210               #   215               #   220Val Thr Pro Gly Phe Cys Ile Cys Pro Pro Gl #y Phe Tyr Gly Val Asn225                 2 #30                 2 #35                 2 #40Cys Asp Lys Ala Asn Cys Ser Thr Thr Cys Ph #e Asn Gly Gly Thr Cys                245   #               250   #               255Phe Tyr Pro Gly Lys Cys Ile Cys Pro Pro Gl #y Leu Glu Gly Glu Gln            260       #           265       #           270Cys Glu Ile Ser Lys Cys Pro Gln Pro Cys Ar #g Asn Gly Gly Lys Cys        275           #       280           #       285Ile Gly Lys Ser Lys Cys Lys Cys Ser Lys Gl #y Tyr Gln Gly Asp Leu    290               #   295               #   300Cys Ser Lys Pro Val Cys Glu Pro Gly Cys Gl #y Ala His Gly Thr Cys305                 3 #10                 3 #15                 3 #20His Glu Pro Asn Lys Cys Gln Cys Gln Glu Gl #y Trp His Gly Arg His                325   #               330   #               335Cys Asn Lys Arg Tyr Glu Ala Ser Leu Ile Hi #s Ala Leu Arg Pro Ala            340       #           345       #           350Gly Ala Gln Leu Arg Gln His Thr Pro Ser Le #u Lys Lys Ala Glu Glu        355           #       360           #       365Arg Arg Asp Pro Pro Glu Ser Asn Tyr Ile Tr #p     370              #   375 <210> SEQ ID NO 5 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 5agggagcacg gacagtgtgc agatgtggac gagtgctcac tagca    #                  #45 <210> SEQ ID NO 6 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 6agagtgtatc tctggctacg c            #                  #                   #21 <210> SEQ ID NO 7 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 7taagtccggc acattacagg tc            #                  #                 22 <210> SEQ ID NO 8 <211> LENGTH: 49 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 8cccacgatgt atgaatggtg gactttgtgt gactcctggt ttctgcatc  #               49 <210> SEQ ID NO 9 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 9aaagacgcat ctgcgagtgt cc            #                  #                 22 <210> SEQ ID NO 10 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 10tgctgatttc acactgctct ccc            #                  #                23 <210> SEQ ID NO 11 <211> LENGTH: 2197<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11cggacgcgtg ggcgtccggc ggtcgcagag ccaggaggcg gaggcgcgcg gg#ccagcctg     60ggccccagcc cacaccttca ccagggccca ggagccacca tgtggcgatg tc#cactgggg    120ctactgctgt tgctgccgct ggctggccac ttggctctgg gtgcccagca gg#gtcgtggg    180cgccgggagc tagcaccggg tctgcacctg cggggcatcc gggacgcggg ag#gccggtac    240tgccaggagc aggacctgtg ctgccgcggc cgtgccgacg actgtgccct gc#cctacctg    300ggcgccatct gttactgtga cctcttctgc aaccgcacgg tctccgactg ct#gccctgac    360ttctgggact tctgcctcgg cgtgccaccc ccttttcccc cgatccaagg at#gtatgcat    420ggaggtcgta tctatccagt cttgggaacg tactgggaca actgtaaccg tt#gcacctgc    480caggagaaca ggcagtggca tggtggatcc agacatgatc aaagccatca ac#cagggcaa    540ctatggctgg caggctggga accacagcgc cttctggggc atgaccctgg at#gagggcat    600tcgctaccgc ctgggcacca tccgcccatc ttcctcggtc atgaacatgc at#gaaattta    660tacagtgctg aacccagggg aggtgcttcc cacagccttc gaggcctctg ag#aagtggcc    720caacctgatt catgagcctc ttgaccaagg caactgtgca ggctcctggg cc#ttctccac    780agcagctgtg gcatccgatc gtgtctcaat ccattctctg ggacacatga cg#cctgtcct    840gtcgccccag aacctgctgt cttgtgacac ccaccagcag cagggctgcc gc#ggtgggcg    900tctcgatggt gcctggtggt tcctgcgtcg ccgaggggtg gtgtctgacc ac#tgctaccc    960cttctcgggc cgtgaacgag acgaggctgg ccctgcgccc ccctgtatga tg#cacagccg   1020agccatgggt cggggcaagc gccaggccac tgcccactgc cccaacagct at#gttaataa   1080caatgacatc taccaggtca ctcctgtcta ccgcctcggc tccaacgaca ag#gagatcat   1140gaaggagctg atggagaatg gccctgtcca agccctcatg gaggtgcatg ag#gacttctt   1200cctatacaag ggaggcatct acagccacac gccagtgagc cttgggaggc ca#gagagata   1260ccgccggcat gggacccact cagtcaagat cacaggatgg ggagaggaga cg#ctgccaga   1320tggaaggacg ctcaaatact ggactgcggc caactcctgg ggcccagcct gg#ggcgagag   1380gggccacttc cgcatcgtgc gcggcgtcaa tgagtgcgac atcgagagct tc#gtgctggg   1440cgtctggggc cgcgtgggca tggaggacat gggtcatcac tgaggctgcg gg#caccacgc   1500ggggtccggc ctgggatcca ggctaagggc cggcggaaga ggccccaatg gg#gcggtgac   1560cccagcctcg cccgacagag cccggggcgc aggcgggcgc cagggcgcta at#cccggcgc   1620gggttccgct gacgcagcgc cccgcctggg agccgcgggc aggcgagact gg#cggagccc   1680ccagacctcc cagtggggac ggggcagggc ctggcctggg aagagcacag ct#gcagatcc   1740caggcctctg gcgcccccac tcaagactac caaagccagg acacctcaag tc#tccagccc   1800caatacccca ccccaatccc gtattctttt tttttttttt ttagacaggg tc#ttgctccg   1860ttgcccaggt tggagtgcag tggcccatca gggctcactg taacctccga ct#cctgggtt   1920caagtgaccc tcccacctca gcctctcaag tagctgggac tacaggtgca cc#accacacc   1980tggctaattt ttgtattttt tgtaaagagg ggggtctcac tgtgttgccc ag#gctggttt   2040cgaactcctg ggctcaagcg gtccacctgc ctccgcctcc caaagtgctg gg#attgcagg   2100catgagccac tgcacccagc cctgtattct tattcttcag atatttattt tt#cttttcac   2160 tgttttaaaa taaaaccaaa gtattgataa aaaaaaa      #                   #    2197 <210> SEQ ID NO 12 <211> LENGTH: 164<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12Met Trp Arg Cys Pro Leu Gly Leu Leu Leu Le #u Leu Pro Leu Ala Gly  1               5  #                 10  #                 15His Leu Ala Leu Gly Ala Gln Gln Gly Arg Gl #y Arg Arg Glu Leu Ala             20      #             25      #             30Pro Gly Leu His Leu Arg Gly Ile Arg Asp Al #a Gly Gly Arg Tyr Cys         35          #         40          #         45Gln Glu Gln Asp Leu Cys Cys Arg Gly Arg Al #a Asp Asp Cys Ala Leu     50              #     55              #     60Pro Tyr Leu Gly Ala Ile Cys Tyr Cys Asp Le #u Phe Cys Asn Arg Thr 65                  # 70                  # 75                  # 80Val Ser Asp Cys Cys Pro Asp Phe Trp Asp Ph #e Cys Leu Gly Val Pro                 85  #                 90  #                 95Pro Pro Phe Pro Pro Ile Gln Gly Cys Met Hi #s Gly Gly Arg Ile Tyr            100       #           105       #           110Pro Val Leu Gly Thr Tyr Trp Asp Asn Cys As #n Arg Cys Thr Cys Gln        115           #       120           #       125Glu Asn Arg Gln Trp His Gly Gly Ser Arg Hi #s Asp Gln Ser His Gln    130               #   135               #   140Pro Gly Gln Leu Trp Leu Ala Gly Trp Glu Pr #o Gln Arg Leu Leu Gly145                 1 #50                 1 #55                 1 #60His Asp Pro Gly <210> SEQ ID NO 13 <211> LENGTH: 533 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (33)<223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base<222> LOCATION: (80) <223> OTHER INFORMATION: a, t, c or g<221> NAME/KEY: modified_base <222> LOCATION: (94)<223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base<222> LOCATION: (144) <223> OTHER INFORMATION: a, t, c or g<221> NAME/KEY: modified_base <222> LOCATION: (188)<223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 13aggctccttg gccctttttc cacagcaagc ttntgcnatc ccgattcgtt gt#ctcaaatc     60caattctctt gggacacatn acgcctgtcc tttngcccca gaacctgctg tc#ttgtacac    120ccaccagcag cagggctgcc gcgntgggcg tctcgatggt gcctggtggt tc#ctgcgtcg    180ccgagggntg gtgtctgacc actgctaccc cttctcgggc cgtgaacgag ac#gaggctgg    240ccctgcgccc ccctgtatga tgcacagccg agccatgggt cggggcaagc gc#caggccac    300tgcccactgc cccaacagct atgttaataa caatgacatc taccaggtca ct#cctgtcta    360ccgcctcggc tccaacgaca aggagatcat gaaggagctg atggagaatg gc#cctgtcca    420agccctcatg gaggtgcatg aggacttctt cctatacaag ggaggcatct ac#agccacac    480gccagtgagc cttgggaggc cagagagata ccgccggcat gggacccact ca#g           533 <210> SEQ ID NO 14 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 14ttcgaggcct ctgagaagtg gccc           #                  #                24 <210> SEQ ID NO 15 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 15ggcggtatct ctctggcctc cc            #                  #                 22 <210> SEQ ID NO 16 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 16ttctccacag cagctgtggc atccgatcgt gtctcaatcc attctctggg  #              50 <210> SEQ ID NO 17 <211> LENGTH: 960 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 17gctgcttgcc ctgttgatgg caggcttggc cctgcagcca ggcactgccc tg#ctgtgcta     60ctcctgcaaa gcccaggtga gcaacgagga ctgcctgcag gtggagaact gc#acccagct    120gggggagcag tgctggaccg cgcgcatccg cgcagttggc ctcctgaccg tc#atcagcaa    180aggctgcagc ttgaactgcg tggatgactc acaggactac tacgtgggca ag#aagaacat    240cacgtgctgt gacaccgact tgtgcaacgc cagcggggcc catgccctgc ag#ccggctgc    300cgccatcctt gcgctgctcc ctgcactcgg cctgctgctc tggggacccg gc#cagctata    360ggctctgggg ggccccgctg cagcccacac tgggtgtggt gccccaggcc tc#tgtgccac    420tcctcacaga cctggcccag tgggagcctg tcctggttcc tgaggcacat cc#taacgcaa    480gtctgaccat gtatgtctgc acccctgtcc cccaccctga ccctcccatg gc#cctctcca    540ggactcccac ccggcagatc agctctagtg acacagatcc gcctgcagat gg#cccctcca    600accctctctg ctgctgtttc catggcccag cattctccac ccttaaccct gt#gctcaggc    660acctcttccc ccaggaagcc ttccctgccc accccatcta tgacttgagc ca#ggtctggt    720ccgtggtgtc ccccgcaccc agcaggggac aggcactcag gagggcccag ta#aaggctga    780gatgaagtgg actgagtaga actggaggac aagagtcgac gtgagttcct gg#gagtctcc    840agagatgggg cctggaggcc tggaggaagg ggccaggcct cacattcgtg gg#gctccctg    900aatggcagcc tgagcacagc gtaggccctt aataaacacc tgttggataa gc#caaaaaaa    960 <210> SEQ ID NO 18 <211> LENGTH: 189 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 18Met Thr His Arg Thr Thr Thr Trp Ala Arg Ar #g Thr Ser Arg Ala Val  1               5  #                 10  #                 15Thr Pro Thr Cys Ala Thr Pro Ala Gly Pro Me #t Pro Cys Ser Arg Leu             20      #             25      #             30Pro Pro Ser Leu Arg Cys Ser Leu His Ser Al #a Cys Cys Ser Gly Asp         35          #         40          #         45Pro Ala Ser Tyr Arg Leu Trp Gly Ala Pro Le #u Gln Pro Thr Leu Gly     50              #     55              #     60Val Val Pro Gln Ala Ser Val Pro Leu Leu Th #r Asp Leu Ala Gln Trp 65                  # 70                  # 75                  # 80Glu Pro Val Leu Val Pro Glu Ala His Pro As #n Ala Ser Leu Thr Met                 85  #                 90  #                 95Tyr Val Cys Thr Pro Val Pro His Pro Asp Pr #o Pro Met Ala Leu Ser            100       #           105       #           110Arg Thr Pro Thr Arg Gln Ile Ser Ser Ser As #p Thr Asp Pro Pro Ala        115           #       120           #       125Asp Gly Pro Ser Asn Pro Leu Cys Cys Cys Ph #e His Gly Pro Ala Phe    130               #   135               #   140Ser Thr Leu Asn Pro Val Leu Arg His Leu Ph #e Pro Gln Glu Ala Phe145                 1 #50                 1 #55                 1 #60Pro Ala His Pro Ile Tyr Asp Leu Ser Gln Va #l Trp Ser Val Val Ser                165   #               170   #               175Pro Ala Pro Ser Arg Gly Gln Ala Leu Arg Ar #g Ala Gln            180       #           185 <210> SEQ ID NO 19<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 19tgctgtgcta ctcctgcaaa gccc           #                  #                24 <210> SEQ ID NO 20 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 20tgcacaagtc ggtgtcacag cacg           #                  #                24 <210> SEQ ID NO 21 <211> LENGTH: 44 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 21agcaacgagg actgcctgca ggtggagaac tgcacccagc tggg    #                  # 44 <210> SEQ ID NO 22 <211> LENGTH: 1200 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 22cccacgcgtc cgaacctctc cagcgatggg agccgcccgc ctgctgccca ac#ctcactct     60gtgcttacag ctgctgattc tctgctgtca aactcagtac gtgagggacc ag#ggcgccat    120gaccgaccag ctgagcaggc ggcagatccg cgagtaccaa ctctacagca gg#accagtgg    180caagcacgtg caggtcaccg ggcgtcgcat ctccgccacc gccgaggacg gc#aacaagtt    240tgccaagctc atagtggaga cggacacgtt tggcagccgg gttcgcatca aa#ggggctga    300gagtgagaag tacatctgta tgaacaagag gggcaagctc atcgggaagc cc#agcgggaa    360gagcaaagac tgcgtgttca cggagatcgt gctggagaac aactatacgg cc#ttccagaa    420cgcccggcac gagggctggt tcatggcctt cacgcggcag gggcggcccc gc#caggcttc    480ccgcagccgc cagaaccagc gcgaggccca cttcatcaag cgcctctacc aa#ggccagct    540gcccttcccc aaccacgccg agaagcagaa gcagttcgag tttgtgggct cc#gcccccac    600ccgccggacc aagcgcacac ggcggcccca gcccctcacg tagtctggga gg#cagggggc    660agcagcccct gggccgcctc cccacccctt tcccttctta atccaaggac tg#ggctgggg    720tggcgggagg ggagccagat ccccgaggga ggaccctgag ggccgcgaag ca#tccgagcc    780cccagctggg aaggggcagg ccggtgcccc aggggcggct ggcacagtgc cc#ccttcccg    840gacgggtggc aggccctgga gaggaactga gtgtcaccct gatctcaggc ca#ccagcctc    900tgccggcctc ccagccgggc tcctgaagcc cgctgaaagg tcagcgactg aa#ggccttgc    960agacaaccgt ctggaggtgg ctgtcctcaa aatctgcttc tcggatctcc ct#cagtctgc   1020ccccagcccc caaactcctc ctggctagac tgtaggaagg gacttttgtt tg#tttgtttg   1080tttcaggaaa aaagaaaggg agagagagga aaatagaggg ttgtccactc ct#cacattcc   1140acgacccagg cctgcacccc acccccaact cccagccccg gaataaaacc at#tttcctgc   1200 <210> SEQ ID NO 23 <211> LENGTH: 205 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 23Met Gly Ala Ala Arg Leu Leu Pro Asn Leu Th #r Leu Cys Leu Gln Leu  1               5  #                 10  #                 15Leu Ile Leu Cys Cys Gln Thr Gln Tyr Val Ar #g Asp Gln Gly Ala Met             20      #             25      #             30Thr Asp Gln Leu Ser Arg Arg Gln Ile Arg Gl #u Tyr Gln Leu Tyr Ser         35          #         40          #         45Arg Thr Ser Gly Lys His Val Gln Val Thr Gl #y Arg Arg Ile Ser Ala     50              #     55              #     60Thr Ala Glu Asp Gly Asn Lys Phe Ala Lys Le #u Ile Val Glu Thr Asp 65                  # 70                  # 75                  # 80Thr Phe Gly Ser Arg Val Arg Ile Lys Gly Al #a Glu Ser Glu Lys Tyr                 85  #                 90  #                 95Ile Cys Met Asn Lys Arg Gly Lys Leu Ile Gl #y Lys Pro Ser Gly Lys            100       #           105       #           110Ser Lys Asp Cys Val Phe Thr Glu Ile Val Le #u Glu Asn Asn Tyr Thr        115           #       120           #       125Ala Phe Gln Asn Ala Arg His Glu Gly Trp Ph #e Met Ala Phe Thr Arg    130               #   135               #   140Gln Gly Arg Pro Arg Gln Ala Ser Arg Ser Ar #g Gln Asn Gln Arg Glu145                 1 #50                 1 #55                 1 #60Ala His Phe Ile Lys Arg Leu Tyr Gln Gly Gl #n Leu Pro Phe Pro Asn                165   #               170   #               175His Ala Glu Lys Gln Lys Gln Phe Glu Phe Va #l Gly Ser Ala Pro Thr            180       #           185       #           190Arg Arg Thr Lys Arg Thr Arg Arg Pro Gln Pr #o Leu Thr        195           #       200           #       205<210> SEQ ID NO 24 <211> LENGTH: 28 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 24cagtacgtga gggaccaggg cgccatga          #                  #             28 <210> SEQ ID NO 25 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 25ccggtgacct gcacgtgctt gcca           #                  #                24 <210> SEQ ID NO 26 <211> LENGTH: 41 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <221> NAME/KEY: modified_base<222> LOCATION: (21) <223> OTHER INFORMATION: a, t, c or g<400> SEQUENCE: 26 gcggatctgc cgcctgctca nctggtcggt catggcgccc t    #                   #   41 <210> SEQ ID NO 27 <211> LENGTH: 2479<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27acttgccatc acctgttgcc agtgtggaaa aattctccct gttgaatttt tt#gcacatgg     60aggacagcag caaagagggc aacacaggct gataagacca gagacagcag gg#agattatt    120ttaccatacg ccctcaggac gttccctcta gctggagttc tggacttcaa ca#gaacccca    180tccagtcatt ttgattttgc tgtttatttt ttttttcttt ttctttttcc ca#ccacattg    240tattttattt ccgtacttca gaaatgggcc tacagaccac aaagtggccc ag#ccatgggg    300cttttttcct gaagtcttgg cttatcattt ccctggggct ctactcacag gt#gtccaaac    360tcctggcctg ccctagtgtg tgccgctgcg acaggaactt tgtctactgt aa#tgagcgaa    420gcttgacctc agtgcctctt gggatcccgg agggcgtaac cgtactctac ct#ccacaaca    480accaaattaa taatgctgga tttcctgcag aactgcacaa tgtacagtcg gt#gcacacgg    540tctacctgta tggcaaccaa ctggacgaat tccccatgaa ccttcccaag aa#tgtcagag    600ttctccattt gcaggaaaac aatattcaga ccatttcacg ggctgctctt gc#ccagctct    660tgaagcttga agagctgcac ctggatgaca actccatatc cacagtgggg gt#ggaagacg    720gggccttccg ggaggctatt agcctcaaat tgttgttttt gtctaagaat ca#cctgagca    780gtgtgcctgt tgggcttcct gtggacttgc aagagctgag agtggatgaa aa#tcgaattg    840ctgtcatatc cgacatggcc ttccagaatc tcacgagctt ggagcgtctt at#tgtggacg    900ggaacctcct gaccaacaag ggtatcgccg agggcacctt cagccatctc ac#caagctca    960aggaattttc aattgtacgt aattcgctgt cccaccctcc tcccgatctc cc#aggtacgc   1020atctgatcag gctctatttg caggacaacc agataaacca cattcctttg ac#agccttct   1080caaatctgcg taagctggaa cggctggata tatccaacaa ccaactgcgg at#gctgactc   1140aaggggtttt tgataatctc tccaacctga agcagctcac tgctcggaat aa#cccttggt   1200tttgtgactg cagtattaaa tgggtcacag aatggctcaa atatatccct tc#atctctca   1260acgtgcgggg tttcatgtgc caaggtcctg aacaagtccg ggggatggcc gt#cagggaat   1320taaatatgaa tcttttgtcc tgtcccacca cgacccccgg cctgcctctc tt#caccccag   1380ccccaagtac agcttctccg accactcagc ctcccaccct ctctattcca aa#ccctagca   1440gaagctacac gcctccaact cctaccacat cgaaacttcc cacgattcct ga#ctgggatg   1500gcagagaaag agtgacccca cctatttctg aacggatcca gctctctatc ca#ttttgtga   1560atgatacttc cattcaagtc agctggctct ctctcttcac cgtgatggca ta#caaactca   1620catgggtgaa aatgggccac agtttagtag ggggcatcgt tcaggagcgc at#agtcagcg   1680gtgagaagca acacctgagc ctggttaact tagagccccg atccacctat cg#gatttgtt   1740tagtgccact ggatgctttt aactaccgcg cggtagaaga caccatttgt tc#agaggcca   1800ccacccatgc ctcctatctg aacaacggca gcaacacagc gtccagccat ga#gcagacga   1860cgtcccacag catgggctcc ccctttctgc tggcgggctt gatcgggggc gc#ggtgatat   1920ttgtgctggt ggtcttgctc agcgtctttt gctggcatat gcacaaaaag gg#gcgctaca   1980cctcccagaa gtggaaatac aaccggggcc ggcggaaaga tgattattgc ga#ggcaggca   2040ccaagaagga caactccatc ctggagatga cagaaaccag ttttcagatc gt#ctccttaa   2100ataacgatca actccttaaa ggagatttca gactgcagcc catttacacc cc#aaatgggg   2160gcattaatta cacagactgc catatcccca acaacatgcg atactgcaac ag#cagcgtgc   2220cagacctgga gcactgccat acgtgacagc cagaggccca gcgttatcaa gg#cggacaat   2280tagactcttg agaacacact cgtgtgtgca cataaagaca cgcagattac at#ttgataaa   2340tgttacacag atgcatttgt gcatttgaat actctgtaat ttatacggtg ta#ctatataa   2400tgggatttaa aaaaagtgct atcttttcta tttcaagtta attacaaaca gt#tttgtaac   2460 tctttgcttt ttaaatctt              #                  #                 247 #9 <210> SEQ ID NO 28 <211> LENGTH: 660<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28Met Gly Leu Gln Thr Thr Lys Trp Pro Ser Hi #s Gly Ala Phe Phe Leu  1               5  #                 10  #                 15Lys Ser Trp Leu Ile Ile Ser Leu Gly Leu Ty #r Ser Gln Val Ser Lys             20      #             25      #             30Leu Leu Ala Cys Pro Ser Val Cys Arg Cys As #p Arg Asn Phe Val Tyr         35          #         40          #         45Cys Asn Glu Arg Ser Leu Thr Ser Val Pro Le #u Gly Ile Pro Glu Gly     50              #     55              #     60Val Thr Val Leu Tyr Leu His Asn Asn Gln Il #e Asn Asn Ala Gly Phe 65                  # 70                  # 75                  # 80Pro Ala Glu Leu His Asn Val Gln Ser Val Hi #s Thr Val Tyr Leu Tyr                 85  #                 90  #                 95Gly Asn Gln Leu Asp Glu Phe Pro Met Asn Le #u Pro Lys Asn Val Arg            100       #           105       #           110Val Leu His Leu Gln Glu Asn Asn Ile Gln Th #r Ile Ser Arg Ala Ala        115           #       120           #       125Leu Ala Gln Leu Leu Lys Leu Glu Glu Leu Hi #s Leu Asp Asp Asn Ser    130               #   135               #   140Ile Ser Thr Val Gly Val Glu Asp Gly Ala Ph #e Arg Glu Ala Ile Ser145                 1 #50                 1 #55                 1 #60Leu Lys Leu Leu Phe Leu Ser Lys Asn His Le #u Ser Ser Val Pro Val                165   #               170   #               175Gly Leu Pro Val Asp Leu Gln Glu Leu Arg Va #l Asp Glu Asn Arg Ile            180       #           185       #           190Ala Val Ile Ser Asp Met Ala Phe Gln Asn Le #u Thr Ser Leu Glu Arg        195           #       200           #       205Leu Ile Val Asp Gly Asn Leu Leu Thr Asn Ly #s Gly Ile Ala Glu Gly    210               #   215               #   220Thr Phe Ser His Leu Thr Lys Leu Lys Glu Ph #e Ser Ile Val Arg Asn225                 2 #30                 2 #35                 2 #40Ser Leu Ser His Pro Pro Pro Asp Leu Pro Gl #y Thr His Leu Ile Arg                245   #               250   #               255Leu Tyr Leu Gln Asp Asn Gln Ile Asn His Il #e Pro Leu Thr Ala Phe            260       #           265       #           270Ser Asn Leu Arg Lys Leu Glu Arg Leu Asp Il #e Ser Asn Asn Gln Leu        275           #       280           #       285Arg Met Leu Thr Gln Gly Val Phe Asp Asn Le #u Ser Asn Leu Lys Gln    290               #   295               #   300Leu Thr Ala Arg Asn Asn Pro Trp Phe Cys As #p Cys Ser Ile Lys Trp305                 3 #10                 3 #15                 3 #20Val Thr Glu Trp Leu Lys Tyr Ile Pro Ser Se #r Leu Asn Val Arg Gly                325   #               330   #               335Phe Met Cys Gln Gly Pro Glu Gln Val Arg Gl #y Met Ala Val Arg Glu            340       #           345       #           350Leu Asn Met Asn Leu Leu Ser Cys Pro Thr Th #r Thr Pro Gly Leu Pro        355           #       360           #       365Leu Phe Thr Pro Ala Pro Ser Thr Ala Ser Pr #o Thr Thr Gln Pro Pro    370               #   375               #   380Thr Leu Ser Ile Pro Asn Pro Ser Arg Ser Ty #r Thr Pro Pro Thr Pro385                 3 #90                 3 #95                 4 #00Thr Thr Ser Lys Leu Pro Thr Ile Pro Asp Tr #p Asp Gly Arg Glu Arg                405   #               410   #               415Val Thr Pro Pro Ile Ser Glu Arg Ile Gln Le #u Ser Ile His Phe Val            420       #           425       #           430Asn Asp Thr Ser Ile Gln Val Ser Trp Leu Se #r Leu Phe Thr Val Met        435           #       440           #       445Ala Tyr Lys Leu Thr Trp Val Lys Met Gly Hi #s Ser Leu Val Gly Gly    450               #   455               #   460Ile Val Gln Glu Arg Ile Val Ser Gly Glu Ly #s Gln His Leu Ser Leu465                 4 #70                 4 #75                 4 #80Val Asn Leu Glu Pro Arg Ser Thr Tyr Arg Il #e Cys Leu Val Pro Leu                485   #               490   #               495Asp Ala Phe Asn Tyr Arg Ala Val Glu Asp Th #r Ile Cys Ser Glu Ala            500       #           505       #           510Thr Thr His Ala Ser Tyr Leu Asn Asn Gly Se #r Asn Thr Ala Ser Ser        515           #       520           #       525His Glu Gln Thr Thr Ser His Ser Met Gly Se #r Pro Phe Leu Leu Ala    530               #   535               #   540Gly Leu Ile Gly Gly Ala Val Ile Phe Val Le #u Val Val Leu Leu Ser545                 5 #50                 5 #55                 5 #60Val Phe Cys Trp His Met His Lys Lys Gly Ar #g Tyr Thr Ser Gln Lys                565   #               570   #               575Trp Lys Tyr Asn Arg Gly Arg Arg Lys Asp As #p Tyr Cys Glu Ala Gly            580       #           585       #           590Thr Lys Lys Asp Asn Ser Ile Leu Glu Met Th #r Glu Thr Ser Phe Gln        595           #       600           #       605Ile Val Ser Leu Asn Asn Asp Gln Leu Leu Ly #s Gly Asp Phe Arg Leu    610               #   615               #   620Gln Pro Ile Tyr Thr Pro Asn Gly Gly Ile As #n Tyr Thr Asp Cys His625                 6 #30                 6 #35                 6 #40Ile Pro Asn Asn Met Arg Tyr Cys Asn Ser Se #r Val Pro Asp Leu Glu                645   #               650   #               655His Cys His Thr             660 <210> SEQ ID NO 29 <211> LENGTH: 21<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 29cggtctacct gtatggcaac c            #                  #                   #21 <210> SEQ ID NO 30 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 30gcaggacaac cagataaacc ac            #                  #                 22 <210> SEQ ID NO 31 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 31acgcagattt gagaaggctg tc            #                  #                 22 <210> SEQ ID NO 32 <211> LENGTH: 46 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 32ttcacgggct gctcttgccc agctcttgaa gcttgaagag ctgcac   #                 46 <210> SEQ ID NO 33 <211> LENGTH: 3449<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33acttggagca agcggcggcg gcggagacag aggcagaggc agaagctggg gc#tccgtcct     60cgcctcccac gagcgatccc cgaggagagc cgcggccctc ggcgaggcga ag#aggccgac    120gaggaagacc cgggtggctg cgcccctgcc tcgcttccca ggcgccggcg gc#tgcagcct    180tgcccctctt gctcgccttg aaaatggaaa agatgctcgc aggctgcttt ct#gctgatcc    240tcggacagat cgtcctcctc cctgccgagg ccagggagcg gtcacgtggg ag#gtccatct    300ctaggggcag acacgctcgg acccacccgc agacggccct tctggagagt tc#ctgtgaga    360acaagcgggc agacctggtt ttcatcattg acagctctcg cagtgtcaac ac#ccatgact    420atgcaaaggt caaggagttc atcgtggaca tcttgcaatt cttggacatt gg#tcctgatg    480tcacccgagt gggcctgctc caatatggca gcactgtcaa gaatgagttc tc#cctcaaga    540ccttcaagag gaagtccgag gtggagcgtg ctgtcaagag gatgcggcat ct#gtccacgg    600gcaccatgac tgggctggcc atccagtatg ccctgaacat cgcattctca ga#agcagagg    660gggcccggcc cctgagggag aatgtgccac gggtcataat gatcgtgaca ga#tgggagac    720ctcaggactc cgtggccgag gtggctgcta aggcacggga cacgggcatc ct#aatctttg    780ccattggtgt gggccaggta gacttcaaca ccttgaagtc cattgggagt ga#gccccatg    840aggaccatgt cttccttgtg gccaatttca gccagattga gacgctgacc tc#cgtgttcc    900agaagaagtt gtgcacggcc cacatgtgca gcaccctgga gcataactgt gc#ccacttct    960gcatcaacat ccctggctca tacgtctgca ggtgcaaaca aggctacatt ct#caactcgg   1020atcagacgac ttgcagaatc caggatctgt gtgccatgga ggaccacaac tg#tgagcagc   1080tctgtgtgaa tgtgccgggc tccttcgtct gccagtgcta cagtggctac gc#cctggctg   1140aggatgggaa gaggtgtgtg gctgtggact actgtgcctc agaaaaccac gg#atgtgaac   1200atgagtgtgt aaatgctgat ggctcctacc tttgccagtg ccatgaagga tt#tgctctta   1260acccagatga aaaaacgtgc acaaggatca actactgtgc actgaacaaa cc#gggctgtg   1320agcatgagtg cgtcaacatg gaggagagct actactgccg ctgccaccgt gg#ctacactc   1380tggaccccaa tggcaaaacc tgcagccgag tggaccactg tgcacagcag ga#ccatggct   1440gtgagcagct gtgtctgaac acggaggatt ccttcgtctg ccagtgctca ga#aggcttcc   1500tcatcaacga ggacctcaag acctgctccc gggtggatta ctgcctgctg ag#tgaccatg   1560gttgtgaata ctcctgtgtc aacatggaca gatcctttgc ctgtcagtgt cc#tgagggac   1620acgtgctccg cagcgatggg aagacgtgtg caaaattgga ctcttgtgct ct#gggggacc   1680acggttgtga acattcgtgt gtaagcagtg aagattcgtt tgtgtgccag tg#ctttgaag   1740gttatatact ccgtgaagat ggaaaaacct gcagaaggaa agatgtctgc ca#agctatag   1800accatggctg tgaacacatt tgtgtgaaca gtgacgactc atacacgtgc ga#gtgcttgg   1860agggattccg gctcgctgag gatgggaaac gctgccgaag gaaggatgtc tg#caaatcaa   1920cccaccatgg ctgcgaacac atttgtgtta ataatgggaa ttcctacatc tg#caaatgct   1980cagagggatt tgttctagct gaggacggaa gacggtgcaa gaaatgcact ga#aggcccaa   2040ttgacctggt ctttgtgatc gatggatcca agagtcttgg agaagagaat tt#tgaggtcg   2100tgaagcagtt tgtcactgga attatagatt ccttgacaat ttcccccaaa gc#cgctcgag   2160tggggctgct ccagtattcc acacaggtcc acacagagtt cactctgaga aa#cttcaact   2220cagccaaaga catgaaaaaa gccgtggccc acatgaaata catgggaaag gg#ctctatga   2280ctgggctggc cctgaaacac atgtttgaga gaagttttac ccaaggagaa gg#ggccaggc   2340ccctttccac aagggtgccc agagcagcca ttgtgttcac cgacggacgg gc#tcaggatg   2400acgtctccga gtgggccagt aaagccaagg ccaatggtat cactatgtat gc#tgttgggg   2460taggaaaagc cattgaggag gaactacaag agattgcctc tgagcccaca aa#caagcatc   2520tcttctatgc cgaagacttc agcacaatgg atgagataag tgaaaaactc aa#gaaaggca   2580tctgtgaagc tctagaagac tccgatggaa gacaggactc tccagcaggg ga#actgccaa   2640aaacggtcca acagccaaca gaatctgagc cagtcaccat aaatatccaa ga#cctacttt   2700cctgttctaa ttttgcagtg caacacagat atctgtttga agaagacaat ct#tttacggt   2760ctacacaaaa gctttcccat tcaacaaaac cttcaggaag ccctttggaa ga#aaaacacg   2820atcaatgcaa atgtgaaaac cttataatgt tccagaacct tgcaaacgaa ga#agtaagaa   2880aattaacaca gcgcttagaa gaaatgacac agagaatgga agccctggaa aa#tcgcctga   2940gatacagatg aagattagaa atcgcgacac atttgtagtc attgtatcac gg#attacaat   3000gaacgcagtg cagagcccca aagctcaggc tattgttaaa tcaataatgt tg#tgaagtaa   3060aacaatcagt actgagaaac ctggtttgcc acagaacaaa gacaagaagt at#acactaac   3120ttgtataaat ttatctagga aaaaaatcct tcagaattct aagatgaatt ta#ccaggtga   3180gaatgaataa gctatgcaag gtattttgta atatactgtg gacacaactt gc#ttctgcct   3240catcctgcct tagtgtgcaa tctcatttga ctatacgata aagtttgcac ag#tcttactt   3300ctgtagaaca ctggccatag gaaatgctgt ttttttgtac tggactttac ct#tgatatat   3360gtatatggat gtatgcataa aatcatagga catatgtact tgtggaacaa gt#tggatttt   3420 ttatacaata ttaaaattca ccacttcag         #                   #          3449 <210> SEQ ID NO 34 <211> LENGTH: 915<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34Met Glu Lys Met Leu Ala Gly Cys Phe Leu Le #u Ile Leu Gly Gln Ile  1               5  #                 10  #                 15Val Leu Leu Pro Ala Glu Ala Arg Glu Arg Se #r Arg Gly Arg Ser Ile             20      #             25      #             30Ser Arg Gly Arg His Ala Arg Thr His Pro Gl #n Thr Ala Leu Leu Glu         35          #         40          #         45Ser Ser Cys Glu Asn Lys Arg Ala Asp Leu Va #l Phe Ile Ile Asp Ser     50              #     55              #     60Ser Arg Ser Val Asn Thr His Asp Tyr Ala Ly #s Val Lys Glu Phe Ile 65                  # 70                  # 75                  # 80Val Asp Ile Leu Gln Phe Leu Asp Ile Gly Pr #o Asp Val Thr Arg Val                 85  #                 90  #                 95Gly Leu Leu Gln Tyr Gly Ser Thr Val Lys As #n Glu Phe Ser Leu Lys            100       #           105       #           110Thr Phe Lys Arg Lys Ser Glu Val Glu Arg Al #a Val Lys Arg Met Arg        115           #       120           #       125His Leu Ser Thr Gly Thr Met Thr Gly Leu Al #a Ile Gln Tyr Ala Leu    130               #   135               #   140Asn Ile Ala Phe Ser Glu Ala Glu Gly Ala Ar #g Pro Leu Arg Glu Asn145                 1 #50                 1 #55                 1 #60Val Pro Arg Val Ile Met Ile Val Thr Asp Gl #y Arg Pro Gln Asp Ser                165   #               170   #               175Val Ala Glu Val Ala Ala Lys Ala Arg Asp Th #r Gly Ile Leu Ile Phe            180       #           185       #           190Ala Ile Gly Val Gly Gln Val Asp Phe Asn Th #r Leu Lys Ser Ile Gly        195           #       200           #       205Ser Glu Pro His Glu Asp His Val Phe Leu Va #l Ala Asn Phe Ser Gln    210               #   215               #   220Ile Glu Thr Leu Thr Ser Val Phe Gln Lys Ly #s Leu Cys Thr Ala His225                 2 #30                 2 #35                 2 #40Met Cys Ser Thr Leu Glu His Asn Cys Ala Hi #s Phe Cys Ile Asn Ile                245   #               250   #               255Pro Gly Ser Tyr Val Cys Arg Cys Lys Gln Gl #y Tyr Ile Leu Asn Ser            260       #           265       #           270Asp Gln Thr Thr Cys Arg Ile Gln Asp Leu Cy #s Ala Met Glu Asp His        275           #       280           #       285Asn Cys Glu Gln Leu Cys Val Asn Val Pro Gl #y Ser Phe Val Cys Gln    290               #   295               #   300Cys Tyr Ser Gly Tyr Ala Leu Ala Glu Asp Gl #y Lys Arg Cys Val Ala305                 3 #10                 3 #15                 3 #20Val Asp Tyr Cys Ala Ser Glu Asn His Gly Cy #s Glu His Glu Cys Val                325   #               330   #               335Asn Ala Asp Gly Ser Tyr Leu Cys Gln Cys Hi #s Glu Gly Phe Ala Leu            340       #           345       #           350Asn Pro Asp Glu Lys Thr Cys Thr Arg Ile As #n Tyr Cys Ala Leu Asn        355           #       360           #       365Lys Pro Gly Cys Glu His Glu Cys Val Asn Me #t Glu Glu Ser Tyr Tyr    370               #   375               #   380Cys Arg Cys His Arg Gly Tyr Thr Leu Asp Pr #o Asn Gly Lys Thr Cys385                 3 #90                 3 #95                 4 #00Ser Arg Val Asp His Cys Ala Gln Gln Asp Hi #s Gly Cys Glu Gln Leu                405   #               410   #               415Cys Leu Asn Thr Glu Asp Ser Phe Val Cys Gl #n Cys Ser Glu Gly Phe            420       #           425       #           430Leu Ile Asn Glu Asp Leu Lys Thr Cys Ser Ar #g Val Asp Tyr Cys Leu        435           #       440           #       445Leu Ser Asp His Gly Cys Glu Tyr Ser Cys Va #l Asn Met Asp Arg Ser    450               #   455               #   460Phe Ala Cys Gln Cys Pro Glu Gly His Val Le #u Arg Ser Asp Gly Lys465                 4 #70                 4 #75                 4 #80Thr Cys Ala Lys Leu Asp Ser Cys Ala Leu Gl #y Asp His Gly Cys Glu                485   #               490   #               495His Ser Cys Val Ser Ser Glu Asp Ser Phe Va #l Cys Gln Cys Phe Glu            500       #           505       #           510Gly Tyr Ile Leu Arg Glu Asp Gly Lys Thr Cy #s Arg Arg Lys Asp Val        515           #       520           #       525Cys Gln Ala Ile Asp His Gly Cys Glu His Il #e Cys Val Asn Ser Asp    530               #   535               #   540Asp Ser Tyr Thr Cys Glu Cys Leu Glu Gly Ph #e Arg Leu Ala Glu Asp545                 5 #50                 5 #55                 5 #60Gly Lys Arg Cys Arg Arg Lys Asp Val Cys Ly #s Ser Thr His His Gly                565   #               570   #               575Cys Glu His Ile Cys Val Asn Asn Gly Asn Se #r Tyr Ile Cys Lys Cys            580       #           585       #           590Ser Glu Gly Phe Val Leu Ala Glu Asp Gly Ar #g Arg Cys Lys Lys Cys        595           #       600           #       605Thr Glu Gly Pro Ile Asp Leu Val Phe Val Il #e Asp Gly Ser Lys Ser    610               #   615               #   620Leu Gly Glu Glu Asn Phe Glu Val Val Lys Gl #n Phe Val Thr Gly Ile625                 6 #30                 6 #35                 6 #40Ile Asp Ser Leu Thr Ile Ser Pro Lys Ala Al #a Arg Val Gly Leu Leu                645   #               650   #               655Gln Tyr Ser Thr Gln Val His Thr Glu Phe Th #r Leu Arg Asn Phe Asn            660       #           665       #           670Ser Ala Lys Asp Met Lys Lys Ala Val Ala Hi #s Met Lys Tyr Met Gly        675           #       680           #       685Lys Gly Ser Met Thr Gly Leu Ala Leu Lys Hi #s Met Phe Glu Arg Ser    690               #   695               #   700Phe Thr Gln Gly Glu Gly Ala Arg Pro Leu Se #r Thr Arg Val Pro Arg705                 7 #10                 7 #15                 7 #20Ala Ala Ile Val Phe Thr Asp Gly Arg Ala Gl #n Asp Asp Val Ser Glu                725   #               730   #               735Trp Ala Ser Lys Ala Lys Ala Asn Gly Ile Th #r Met Tyr Ala Val Gly            740       #           745       #           750Val Gly Lys Ala Ile Glu Glu Glu Leu Gln Gl #u Ile Ala Ser Glu Pro        755           #       760           #       765Thr Asn Lys His Leu Phe Tyr Ala Glu Asp Ph #e Ser Thr Met Asp Glu    770               #   775               #   780Ile Ser Glu Lys Leu Lys Lys Gly Ile Cys Gl #u Ala Leu Glu Asp Ser785                 7 #90                 7 #95                 8 #00Asp Gly Arg Gln Asp Ser Pro Ala Gly Glu Le #u Pro Lys Thr Val Gln                805   #               810   #               815Gln Pro Thr Glu Ser Glu Pro Val Thr Ile As #n Ile Gln Asp Leu Leu            820       #           825       #           830Ser Cys Ser Asn Phe Ala Val Gln His Arg Ty #r Leu Phe Glu Glu Asp        835           #       840           #       845Asn Leu Leu Arg Ser Thr Gln Lys Leu Ser Hi #s Ser Thr Lys Pro Ser    850               #   855               #   860Gly Ser Pro Leu Glu Glu Lys His Asp Gln Cy #s Lys Cys Glu Asn Leu865                 8 #70                 8 #75                 8 #80Ile Met Phe Gln Asn Leu Ala Asn Glu Glu Va #l Arg Lys Leu Thr Gln                885   #               890   #               895Arg Leu Glu Glu Met Thr Gln Arg Met Glu Al #a Leu Glu Asn Arg Leu            900       #           905       #           910 Arg Tyr Arg        915 <210> SEQ ID NO 35 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 35gtgaccctgg ttgtgaatac tcc            #                  #                23 <210> SEQ ID NO 36 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 36acagccatgg tctatagctt gg            #                  #                 22 <210> SEQ ID NO 37 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 37gcctgtcagt gtcctgaggg acacgtgctc cgcagcgatg ggaag    #                  #45 <210> SEQ ID NO 38 <211> LENGTH: 1813 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 38ggagccgccc tgggtgtcag cggctcggct cccgcgcacg ctccggccgt cg#cgcagcct     60cggcacctgc aggtccgtgc gtcccgcggc tggcgcccct gactccgtcc cg#gccaggga    120gggccatgat ttccctcccg gggcccctgg tgaccaactt gctgcggttt tt#gttcctgg    180ggctgagtgc cctcgcgccc ccctcgcggg cccagctgca actgcacttg cc#cgccaacc    240ggttgcaggc ggtggaggga ggggaagtgg tgcttccagc gtggtacacc tt#gcacgggg    300aggtgtcttc atcccagcca tgggaggtgc cctttgtgat gtggttcttc aa#acagaaag    360aaaaggagga tcaggtgttg tcctacatca atggggtcac aacaagcaaa cc#tggagtat    420ccttggtcta ctccatgccc tcccggaacc tgtccctgcg gctggagggt ct#ccaggaga    480aagactctgg cccctacagc tgctccgtga atgtgcaaga caaacaaggc aa#atctaggg    540gccacagcat caaaacctta gaactcaatg tactggttcc tccagctcct cc#atcctgcc    600gtctccaggg tgtgccccat gtgggggcaa acgtgaccct gagctgccag tc#tccaagga    660gtaagcccgc tgtccaatac cagtgggatc ggcagcttcc atccttccag ac#tttctttg    720caccagcatt agatgtcatc cgtgggtctt taagcctcac caacctttcg tc#ttccatgg    780ctggagtcta tgtctgcaag gcccacaatg aggtgggcac tgcccaatgt aa#tgtgacgc    840tggaagtgag cacagggcct ggagctgcag tggttgctgg agctgttgtg gg#taccctgg    900ttggactggg gttgctggct gggctggtcc tcttgtacca ccgccggggc aa#ggccctgg    960aggagccagc caatgatatc aaggaggatg ccattgctcc ccggaccctg cc#ctggccca   1020agagctcaga cacaatctcc aagaatggga ccctttcctc tgtcacctcc gc#acgagccc   1080tccggccacc ccatggccct cccaggcctg gtgcattgac ccccacgccc ag#tctctcca   1140gccaggccct gccctcacca agactgccca cgacagatgg ggcccaccct ca#accaatat   1200cccccatccc tggtggggtt tcttcctctg gcttgagccg catgggtgct gt#gcctgtga   1260tggtgcctgc ccagagtcaa gctggctctc tggtatgatg accccaccac tc#attggcta   1320aaggatttgg ggtctctcct tcctataagg gtcacctcta gcacagaggc ct#gagtcatg   1380ggaaagagtc acactcctga cccttagtac tctgccccca cctctcttta ct#gtgggaaa   1440accatctcag taagacctaa gtgtccagga gacagaagga gaagaggaag tg#gatctgga   1500attgggagga gcctccaccc acccctgact cctccttatg aagccagctg ct#gaaattag   1560ctactcacca agagtgaggg gcagagactt ccagtcactg agtctcccag gc#ccccttga   1620tctgtacccc acccctatct aacaccaccc ttggctccca ctccagctcc ct#gtattgat   1680ataacctgtc aggctggctt ggttaggttt tactggggca gaggataggg aa#tctcttat   1740taaaactaac atgaaatatg tgttgttttc atttgcaaat ttaaataaag at#acataatg   1800 tttgtatgaa aaa               #                  #                   #    1813 <210> SEQ ID NO 39 <211> LENGTH: 390<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39Met Ile Ser Leu Pro Gly Pro Leu Val Thr As #n Leu Leu Arg Phe Leu  1               5  #                 10  #                 15Phe Leu Gly Leu Ser Ala Leu Ala Pro Pro Se #r Arg Ala Gln Leu Gln             20      #             25      #             30Leu His Leu Pro Ala Asn Arg Leu Gln Ala Va #l Glu Gly Gly Glu Val         35          #         40          #         45Val Leu Pro Ala Trp Tyr Thr Leu His Gly Gl #u Val Ser Ser Ser Gln     50              #     55              #     60Pro Trp Glu Val Pro Phe Val Met Trp Phe Ph #e Lys Gln Lys Glu Lys 65                  # 70                  # 75                  # 80Glu Asp Gln Val Leu Ser Tyr Ile Asn Gly Va #l Thr Thr Ser Lys Pro                 85  #                 90  #                 95Gly Val Ser Leu Val Tyr Ser Met Pro Ser Ar #g Asn Leu Ser Leu Arg            100       #           105       #           110Leu Glu Gly Leu Gln Glu Lys Asp Ser Gly Pr #o Tyr Ser Cys Ser Val        115           #       120           #       125Asn Val Gln Asp Lys Gln Gly Lys Ser Arg Gl #y His Ser Ile Lys Thr    130               #   135               #   140Leu Glu Leu Asn Val Leu Val Pro Pro Ala Pr #o Pro Ser Cys Arg Leu145                 1 #50                 1 #55                 1 #60Gln Gly Val Pro His Val Gly Ala Asn Val Th #r Leu Ser Cys Gln Ser                165   #               170   #               175Pro Arg Ser Lys Pro Ala Val Gln Tyr Gln Tr #p Asp Arg Gln Leu Pro            180       #           185       #           190Ser Phe Gln Thr Phe Phe Ala Pro Ala Leu As #p Val Ile Arg Gly Ser        195           #       200           #       205Leu Ser Leu Thr Asn Leu Ser Ser Ser Met Al #a Gly Val Tyr Val Cys    210               #   215               #   220Lys Ala His Asn Glu Val Gly Thr Ala Gln Cy #s Asn Val Thr Leu Glu225                 2 #30                 2 #35                 2 #40Val Ser Thr Gly Pro Gly Ala Ala Val Val Al #a Gly Ala Val Val Gly                245   #               250   #               255Thr Leu Val Gly Leu Gly Leu Leu Ala Gly Le #u Val Leu Leu Tyr His            260       #           265       #           270Arg Arg Gly Lys Ala Leu Glu Glu Pro Ala As #n Asp Ile Lys Glu Asp        275           #       280           #       285Ala Ile Ala Pro Arg Thr Leu Pro Trp Pro Ly #s Ser Ser Asp Thr Ile    290               #   295               #   300Ser Lys Asn Gly Thr Leu Ser Ser Val Thr Se #r Ala Arg Ala Leu Arg305                 3 #10                 3 #15                 3 #20Pro Pro His Gly Pro Pro Arg Pro Gly Ala Le #u Thr Pro Thr Pro Ser                325   #               330   #               335Leu Ser Ser Gln Ala Leu Pro Ser Pro Arg Le #u Pro Thr Thr Asp Gly            340       #           345       #           350Ala His Pro Gln Pro Ile Ser Pro Ile Pro Gl #y Gly Val Ser Ser Ser        355           #       360           #       365Gly Leu Ser Arg Met Gly Ala Val Pro Val Me #t Val Pro Ala Gln Ser    370               #   375               #   380Gln Ala Gly Ser Leu Val 385                 3 #90 <210> SEQ ID NO 40<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 40agggtctcca ggagaaagac tc            #                  #                 22 <210> SEQ ID NO 41 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 41attgtgggcc ttgcagacat agac           #                  #                24 <210> SEQ ID NO 42 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 42ggccacagca tcaaaacctt agaactcaat gtactggttc ctccagctcc  #              50 <210> SEQ ID NO 43 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 43gtgtgacaca gcgtgggc              #                   #                  #  18 <210> SEQ ID NO 44 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 44gaccggcagg cttctgcg              #                   #                  #  18 <210> SEQ ID NO 45 <211> LENGTH: 25 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 45cagcagcttc agccaccagg agtgg           #                  #               25 <210> SEQ ID NO 46 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 46ctgagccgtg ggctgcagtc tcgc           #                  #                24 <210> SEQ ID NO 47 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 47ccgactacga ctggttcttc atcatgcagg atgacacata tgtgc    #                  #45 <210> SEQ ID NO 48 <211> LENGTH: 2822 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 48cgccaccact gcggccaccg ccaatgaaac gcctcccgct cctagtggtt tt#ttccactt     60tgttgaattg ttcctatact caaaattgca ccaagacacc ttgtctccca aa#tgcaaaat    120gtgaaatacg caatggaatt gaagcctgct attgcaacat gggattttca gg#aaatggtg    180tcacaatttg tgaagatgat aatgaatgtg gaaatttaac tcagtcctgt gg#cgaaaatg    240ctaattgcac taacacagaa ggaagttatt attgtatgtg tgtacctggc tt#cagatcca    300gcagtaacca agacaggttt atcactaatg atggaaccgt ctgtatagaa aa#tgtgaatg    360caaactgcca tttagataat gtctgtatag ctgcaaatat taataaaact tt#aacaaaaa    420tcagatccat aaaagaacct gtggctttgc tacaagaagt ctatagaaat tc#tgtgacag    480atctttcacc aacagatata attacatata tagaaatatt agctgaatca tc#ttcattac    540taggttacaa gaacaacact atctcagcca aggacaccct ttctaactca ac#tcttactg    600aatttgtaaa aaccgtgaat aattttgttc aaagggatac atttgtagtt tg#ggacaagt    660tatctgtgaa tcataggaga acacatctta caaaactcat gcacactgtt ga#acaagcta    720ctttaaggat atcccagagc ttccaaaaga ccacagagtt tgatacaaat tc#aacggata    780tagctctcaa agttttcttt tttgattcat ataacatgaa acatattcat cc#tcatatga    840atatggatgg agactacata aatatatttc caaagagaaa agctgcatat ga#ttcaaatg    900gcaatgttgc agttgcattt ttatattata agagtattgg tcctttgctt tc#atcatctg    960acaacttctt attgaaacct caaaattatg ataattctga agaggaggaa ag#agtcatat   1020cttcagtaat ttcagtctca atgagctcaa acccacccac attatatgaa ct#tgaaaaaa   1080taacatttac attaagtcat cgaaaggtca cagataggta taggagtcta tg#tgcatttt   1140ggaattactc acctgatacc atgaatggca gctggtcttc agagggctgt ga#gctgacat   1200actcaaatga gacccacacc tcatgccgct gtaatcacct gacacatttt gc#aattttga   1260tgtcctctgg tccttccatt ggtattaaag attataatat tcttacaagg at#cactcaac   1320taggaataat tatttcactg atttgtcttg ccatatgcat ttttaccttc tg#gttcttca   1380gtgaaattca aagcaccagg acaacaattc acaaaaatct ttgctgtagc ct#atttcttg   1440ctgaacttgt ttttcttgtt gggatcaata caaatactaa taagctcttc tg#ttcaatca   1500ttgccggact gctacactac ttctttttag ctgcttttgc atggatgtgc at#tgaaggca   1560tacatctcta tctcattgtt gtgggtgtca tctacaacaa gggatttttg ca#caagaatt   1620tttatatctt tggctatcta agcccagccg tggtagttgg attttcggca gc#actaggat   1680acagatatta tggcacaacc aaagtatgtt ggcttagcac cgaaaacaac tt#tatttgga   1740gttttatagg accagcatgc ctaatcattc ttgttaatct cttggctttt gg#agtcatca   1800tatacaaagt ttttcgtcac actgcagggt tgaaaccaga agttagttgc tt#tgagaaca   1860taaggtcttg tgcaagagga gccctcgctc ttctgttcct tctcggcacc ac#ctggatct   1920ttggggttct ccatgttgtg cacgcatcag tggttacagc ttacctcttc ac#agtcagca   1980atgctttcca ggggatgttc atttttttat tcctgtgtgt tttatctaga aa#gattcaag   2040aagaatatta cagattgttc aaaaatgtcc cctgttgttt tggatgttta ag#gtaaacat   2100agagaatggt ggataattac aactgcacaa aaataaaaat tccaagctgt gg#atgaccaa   2160tgtataaaaa tgactcatca aattatccaa ttattaacta ctagacaaaa ag#tattttaa   2220atcagttttt ctgtttatgc tataggaact gtagataata aggtaaaatt at#gtatcata   2280tagatatact atgtttttct atgtgaaata gttctgtcaa aaatagtatt gc#agatattt   2340ggaaagtaat tggtttctca ggagtgatat cactgcaccc aaggaaagat tt#tctttcta   2400acacgagaag tatatgaatg tcctgaagga aaccactggc ttgatatttc tg#tgactcgt   2460gttgcctttg aaactagtcc cctaccacct cggtaatgag ctccattaca ga#aagtggaa   2520cataagagaa tgaaggggca gaatatcaaa cagtgaaaag ggaatgataa ga#tgtatttt   2580gaatgaactg ttttttctgt agactagctg agaaattgtt gacataaaat aa#agaattga   2640agaaacacat tttaccattt tgtgaattgt tctgaactta aatgtccact aa#aacaactt   2700agacttctgt ttgctaaatc tgtttctttt tctaatattc taaaaaaaaa aa#aaaggttt   2760acctccacaa attgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa#aaaaaaaa   2820 aa                   #                  #                   #            2822 <210> SEQ ID NO 49<211> LENGTH: 690 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 49 Met Lys Arg Leu Pro Leu Leu Val Val Phe Se#r Thr Leu Leu Asn Cys   1               5  #                 10 #                 15 Ser Tyr Thr Gln Asn Cys Thr Lys Thr Pro Cy#s Leu Pro Asn Ala Lys              20      #             25     #             30 Cys Glu Ile Arg Asn Gly Ile Glu Ala Cys Ty#r Cys Asn Met Gly Phe          35          #         40         #         45 Ser Gly Asn Gly Val Thr Ile Cys Glu Asp As#p Asn Glu Cys Gly Asn      50              #     55             #     60 Leu Thr Gln Ser Cys Gly Glu Asn Ala Asn Cy#s Thr Asn Thr Glu Gly  65                  # 70                 # 75                  # 80 Ser Tyr Tyr Cys Met Cys Val Pro Gly Phe Ar#g Ser Ser Ser Asn Gln                  85  #                 90 #                 95 Asp Arg Phe Ile Thr Asn Asp Gly Thr Val Cy#s Ile Glu Asn Val Asn             100       #           105      #           110 Ala Asn Cys His Leu Asp Asn Val Cys Ile Al#a Ala Asn Ile Asn Lys         115           #       120          #       125 Thr Leu Thr Lys Ile Arg Ser Ile Lys Glu Pr#o Val Ala Leu Leu Gln     130               #   135              #   140 Glu Val Tyr Arg Asn Ser Val Thr Asp Leu Se#r Pro Thr Asp Ile Ile 145                 1 #50                 1#55                 1 #60 Thr Tyr Ile Glu Ile Leu Ala Glu Ser Ser Se#r Leu Leu Gly Tyr Lys                 165   #               170  #               175 Asn Asn Thr Ile Ser Ala Lys Asp Thr Leu Se#r Asn Ser Thr Leu Thr             180       #           185      #           190 Glu Phe Val Lys Thr Val Asn Asn Phe Val Gl#n Arg Asp Thr Phe Val         195           #       200          #       205 Val Trp Asp Lys Leu Ser Val Asn His Arg Ar#g Thr His Leu Thr Lys     210               #   215              #   220 Leu Met His Thr Val Glu Gln Ala Thr Leu Ar#g Ile Ser Gln Ser Phe 225                 2 #30                 2#35                 2 #40 Gln Lys Thr Thr Glu Phe Asp Thr Asn Ser Th#r Asp Ile Ala Leu Lys                 245   #               250  #               255 Val Phe Phe Phe Asp Ser Tyr Asn Met Lys Hi#s Ile His Pro His Met             260       #           265      #           270 Asn Met Asp Gly Asp Tyr Ile Asn Ile Phe Pr#o Lys Arg Lys Ala Ala         275           #       280          #       285 Tyr Asp Ser Asn Gly Asn Val Ala Val Ala Ph#e Leu Tyr Tyr Lys Ser     290               #   295              #   300 Ile Gly Pro Leu Leu Ser Ser Ser Asp Asn Ph#e Leu Leu Lys Pro Gln 305                 3 #10                 3#15                 3 #20 Asn Tyr Asp Asn Ser Glu Glu Glu Glu Arg Va#l Ile Ser Ser Val Ile                 325   #               330  #               335 Ser Val Ser Met Ser Ser Asn Pro Pro Thr Le#u Tyr Glu Leu Glu Lys             340       #           345      #           350 Ile Thr Phe Thr Leu Ser His Arg Lys Val Th#r Asp Arg Tyr Arg Ser         355           #       360          #       365 Leu Cys Ala Phe Trp Asn Tyr Ser Pro Asp Th#r Met Asn Gly Ser Trp     370               #   375              #   380 Ser Ser Glu Gly Cys Glu Leu Thr Tyr Ser As#n Glu Thr His Thr Ser 385                 3 #90                 3#95                 4 #00 Cys Arg Cys Asn His Leu Thr His Phe Ala Il#e Leu Met Ser Ser Gly                 405   #               410  #               415 Pro Ser Ile Gly Ile Lys Asp Tyr Asn Ile Le#u Thr Arg Ile Thr Gln             420       #           425      #           430 Leu Gly Ile Ile Ile Ser Leu Ile Cys Leu Al#a Ile Cys Ile Phe Thr         435           #       440          #       445 Phe Trp Phe Phe Ser Glu Ile Gln Ser Thr Ar#g Thr Thr Ile His Lys     450               #   455              #   460 Asn Leu Cys Cys Ser Leu Phe Leu Ala Glu Le#u Val Phe Leu Val Gly 465                 4 #70                 4#75                 4 #80 Ile Asn Thr Asn Thr Asn Lys Leu Phe Cys Se#r Ile Ile Ala Gly Leu                 485   #               490  #               495 Leu His Tyr Phe Phe Leu Ala Ala Phe Ala Tr#p Met Cys Ile Glu Gly             500       #           505      #           510 Ile His Leu Tyr Leu Ile Val Val Gly Val Il#e Tyr Asn Lys Gly Phe         515           #       520          #       525 Leu His Lys Asn Phe Tyr Ile Phe Gly Tyr Le#u Ser Pro Ala Val Val     530               #   535              #   540 Val Gly Phe Ser Ala Ala Leu Gly Tyr Arg Ty#r Tyr Gly Thr Thr Lys 545                 5 #50                 5#55                 5 #60 Val Cys Trp Leu Ser Thr Glu Asn Asn Phe Il#e Trp Ser Phe Ile Gly                 565   #               570  #               575 Pro Ala Cys Leu Ile Ile Leu Val Asn Leu Le#u Ala Phe Gly Val Ile             580       #           585      #           590 Ile Tyr Lys Val Phe Arg His Thr Ala Gly Le#u Lys Pro Glu Val Ser         595           #       600          #       605 Cys Phe Glu Asn Ile Arg Ser Cys Ala Arg Gl#y Ala Leu Ala Leu Leu     610               #   615              #   620 Phe Leu Leu Gly Thr Thr Trp Ile Phe Gly Va#l Leu His Val Val His 625                 6 #30                 6#35                 6 #40 Ala Ser Val Val Thr Ala Tyr Leu Phe Thr Va#l Ser Asn Ala Phe Gln                 645   #               650  #               655 Gly Met Phe Ile Phe Leu Phe Leu Cys Val Le#u Ser Arg Lys Ile Gln             660       #           665      #           670 Glu Glu Tyr Tyr Arg Leu Phe Lys Asn Val Pr#o Cys Cys Phe Gly Cys         675           #       680          #       685 Leu Arg     690 <210> SEQ ID NO 50 <211> LENGTH: 589<212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (61)<223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 50tggaaacata tcctccctca tatgaatatg gatggagact acataaatat at#ttccaaag     60ngaaaagccg gcatatggat tcaaatggca atgttgcagt tgcattttta ta#ttataaga    120gtattggtcc ctttgctttc atcatctgac aacttcttat tgaaacctca aa#attatgat    180aattctgaag aggaggaaag agtcatatct tcagtaattt cagtctcaat ga#gctcaaac    240ccacccacat tatatgaact tgaaaaaata acatttacat taagtcatcg aa#aggtcaca    300gataggtata ggagtctatg tggcattttg gaatactcac ctgataccat ga#atggcagc    360tggtcttcag agggctgtga gctgacatac tcaaatgaga cccacacctc at#gccgctgt    420aatcacctga cacattttgc aattttgatg tcctctggtc cttccattgg ta#ttaaagat    480tataatattc ttacaaggat cactcaacta ggaataatta tttcactgat tt#gtcttgcc    540 atatgcattt ttaccttctg gttcttcagt gaaattcaaa gcaccagga  #              589 <210> SEQ ID NO 51 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 51ggtaatgagc tccattacag             #                  #                   # 20 <210> SEQ ID NO 52 <211> LENGTH: 18<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 52ggagtagaaa gcgcatgg              #                   #                  #  18 <210> SEQ ID NO 53 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 53cacctgatac catgaatggc ag            #                  #                 22 <210> SEQ ID NO 54 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 54cgagctcgaa ttaattcg              #                   #                  #  18 <210> SEQ ID NO 55 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 55ggatctcctg agctcagg              #                   #                  #  18 <210> SEQ ID NO 56 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 56cctagttgag tgatccttgt aag            #                  #                23 <210> SEQ ID NO 57 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 57atgagaccca cacctcatgc cgctgtaatc acctgacaca ttttgcaatt  #              50 <210> SEQ ID NO 58 <211> LENGTH: 2137 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 58gctcccagcc aagaacctcg gggccgctgc gcggtgggga ggagttcccc ga#aacccggc     60cgctaagcga ggcctcctcc tcccgcagat ccgaacggcc tgggcggggt ca#ccccggct    120gggacaagaa gccgccgcct gcctgcccgg gcccggggag ggggctgggg ct#ggggccgg    180aggcggggtg tgagtgggtg tgtgcggggg gcggaggctt gatgcaatcc cg#ataagaaa    240tgctcgggtg tcttgggcac ctacccgtgg ggcccgtaag gcgctactat at#aaggctgc    300cggcccggag ccgccgcgcc gtcagagcag gagcgctgcg tccaggatct ag#ggccacga    360ccatcccaac ccggcactca cagccccgca gcgcatcccg gtcgccgccc ag#cctcccgc    420acccccatcg ccggagctgc gccgagagcc ccagggaggt gccatgcgga gc#gggtgtgt    480ggtggtccac gtatggatcc tggccggcct ctggctggcc gtggccgggc gc#cccctcgc    540cttctcggac gcggggcccc acgtgcacta cggctggggc gaccccatcc gc#ctgcggca    600cctgtacacc tccggccccc acgggctctc cagctgcttc ctgcgcatcc gt#gccgacgg    660cgtcgtggac tgcgcgcggg gccagagcgc gcacagtttg ctggagatca ag#gcagtcgc    720tctgcggacc gtggccatca agggcgtgca cagcgtgcgg tacctctgca tg#ggcgccga    780cggcaagatg caggggctgc ttcagtactc ggaggaagac tgtgctttcg ag#gaggagat    840ccgcccagat ggctacaatg tgtaccgatc cgagaagcac cgcctcccgg tc#tccctgag    900cagtgccaaa cagcggcagc tgtacaagaa cagaggcttt cttccactct ct#catttcct    960gcccatgctg cccatggtcc cagaggagcc tgaggacctc aggggccact tg#gaatctga   1020catgttctct tcgcccctgg agaccgacag catggaccca tttgggcttg tc#accggact   1080ggaggccgtg aggagtccca gctttgagaa gtaactgaga ccatgcccgg gc#ctcttcac   1140tgctgccagg ggctgtggta cctgcagcgt gggggacgtg cttctacaag aa#cagtcctg   1200agtccacgtt ctgtttagct ttaggaagaa acatctagaa gttgtacata tt#cagagttt   1260tccattggca gtgccagttt ctagccaata gacttgtctg atcataacat tg#taagcctg   1320tagcttgccc agctgctgcc tgggccccca ttctgctccc tcgaggttgc tg#gacaagct   1380gctgcactgt ctcagttctg cttgaatacc tccatcgatg gggaactcac tt#cctttgga   1440aaaattctta tgtcaagctg aaattctcta attttttctc atcacttccc ca#ggagcagc   1500cagaagacag gcagtagttt taatttcagg aacaggtgat ccactctgta aa#acagcagg   1560taaatttcac tcaaccccat gtgggaattg atctatatct ctacttccag gg#accatttg   1620cccttcccaa atccctccag gccagaactg actggagcag gcatggccca cc#aggcttca   1680ggagtagggg aagcctggag ccccactcca gccctgggac aacttgagaa tt#ccccctga   1740ggccagttct gtcatggatg ctgtcctgag aataacttgc tgtcccggtg tc#acctgctt   1800ccatctccca gcccaccagc cctctgccca cctcacatgc ctccccatgg at#tggggcct   1860cccaggcccc ccaccttatg tcaacctgca cttcttgttc aaaaatcagg aa#aagaaaag   1920atttgaagac cccaagtctt gtcaataact tgctgtgtgg aagcagcggg gg#aagaccta   1980gaaccctttc cccagcactt ggttttccaa catgatattt atgagtaatt ta#ttttgata   2040tgtacatctc ttattttctt acattattta tgcccccaaa ttatatttat gt#atgtaagt   2100 gaggtttgtt ttgtatatta aaatggagtt tgtttgt      #                   #    2137 <210> SEQ ID NO 59 <211> LENGTH: 216<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59Met Arg Ser Gly Cys Val Val Val His Val Tr #p Ile Leu Ala Gly Leu  1               5  #                 10  #                 15Trp Leu Ala Val Ala Gly Arg Pro Leu Ala Ph #e Ser Asp Ala Gly Pro             20      #             25      #             30His Val His Tyr Gly Trp Gly Asp Pro Ile Ar #g Leu Arg His Leu Tyr         35          #         40          #         45Thr Ser Gly Pro His Gly Leu Ser Ser Cys Ph #e Leu Arg Ile Arg Ala     50              #     55              #     60Asp Gly Val Val Asp Cys Ala Arg Gly Gln Se #r Ala His Ser Leu Leu 65                  # 70                  # 75                  # 80Glu Ile Lys Ala Val Ala Leu Arg Thr Val Al #a Ile Lys Gly Val His                 85  #                 90  #                 95Ser Val Arg Tyr Leu Cys Met Gly Ala Asp Gl #y Lys Met Gln Gly Leu            100       #           105       #           110Leu Gln Tyr Ser Glu Glu Asp Cys Ala Phe Gl #u Glu Glu Ile Arg Pro        115           #       120           #       125Asp Gly Tyr Asn Val Tyr Arg Ser Glu Lys Hi #s Arg Leu Pro Val Ser    130               #   135               #   140Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Ly #s Asn Arg Gly Phe Leu145                 1 #50                 1 #55                 1 #60Pro Leu Ser His Phe Leu Pro Met Leu Pro Me #t Val Pro Glu Glu Pro                165   #               170   #               175Glu Asp Leu Arg Gly His Leu Glu Ser Asp Me #t Phe Ser Ser Pro Leu            180       #           185       #           190Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Va #l Thr Gly Leu Glu Ala        195           #       200           #       205Val Arg Ser Pro Ser Phe Glu Lys     210               #   215<210> SEQ ID NO 60 <211> LENGTH: 26 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 60atccgcccag atggctacaa tgtgta           #                  #              26 <210> SEQ ID NO 61 <211> LENGTH: 42 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 61gcctcccggt ctccctgagc agtgccaaac agcggcagtg ta     #                  #  42 <210> SEQ ID NO 62 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 62ccagtccggt gacaagccca aa            #                  #                 22 <210> SEQ ID NO 63 <211> LENGTH: 1295<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63cccagaagtt caagggcccc cggcctcctg cgctcctgcc gccgggaccc tc#gacctcct     60cagagcagcc ggctgccgcc ccgggaagat ggcgaggagg agccgccacc gc#ctcctcct    120gctgctgctg cgctacctgg tggtcgccct gggctatcat aaggcctatg gg#ttttctgc    180cccaaaagac caacaagtag tcacagcagt agagtaccaa gaggctattt ta#gcctgcaa    240aaccccaaag aagactgttt cctccagatt agagtggaag aaactgggtc gg#agtgtctc    300ctttgtctac tatcaacaga ctcttcaagg tgattttaaa aatcgagctg ag#atgataga    360tttcaatatc cggatcaaaa atgtgacaag aagtgatgcg gggaaatatc gt#tgtgaagt    420tagtgcccca tctgagcaag gccaaaacct ggaagaggat acagtcactc tg#gaagtatt    480agtggctcca gcagttccat catgtgaagt accctcttct gctctgagtg ga#actgtggt    540agagctacga tgtcaagaca aagaagggaa tccagctcct gaatacacat gg#tttaagga    600tggcatccgt ttgctagaaa atcccagact tggctcccaa agcaccaaca gc#tcatacac    660aatgaataca aaaactggaa ctctgcaatt taatactgtt tccaaactgg ac#actggaga    720atattcctgt gaagcccgca attctgttgg atatcgcagg tgtcctggga aa#cgaatgca    780agtagatgat ctcaacataa gtggcatcat agcagccgta gtagttgtgg cc#ttagtgat    840ttccgtttgt ggccttggtg tatgctatgc tcagaggaaa ggctactttt ca#aaagaaac    900ctccttccag aagagtaatt cttcatctaa agccacgaca atgagtgaaa at#gtgcagtg    960gctcacgcct gtaatcccag cactttggaa ggccgcggcg ggcggatcac ga#ggtcagga   1020gttctagacc agtctggcca atatggtgaa accccatctc tactaaaata ca#aaaattag   1080ctgggcatgg tggcatgtgc ctgcagttcc agctgcttgg gagacaggag aa#tcacttga   1140acccgggagg cggaggttgc agtgagctga gatcacgcca ctgcagtcca gc#ctgggtaa   1200cagagcaaga ttccatctca aaaaataaaa taaataaata aataaatact gg#tttttacc   1260 tgtagaattc ttacaataaa tatagcttga tattc       #                   #     1295 <210> SEQ ID NO 64 <211> LENGTH: 312<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64Met Ala Arg Arg Ser Arg His Arg Leu Leu Le #u Leu Leu Leu Arg Tyr  1               5  #                 10  #                 15Leu Val Val Ala Leu Gly Tyr His Lys Ala Ty #r Gly Phe Ser Ala Pro             20      #             25      #             30Lys Asp Gln Gln Val Val Thr Ala Val Glu Ty #r Gln Glu Ala Ile Leu         35          #         40          #         45Ala Cys Lys Thr Pro Lys Lys Thr Val Ser Se #r Arg Leu Glu Trp Lys     50              #     55              #     60Lys Leu Gly Arg Ser Val Ser Phe Val Tyr Ty #r Gln Gln Thr Leu Gln 65                  # 70                  # 75                  # 80Gly Asp Phe Lys Asn Arg Ala Glu Met Ile As #p Phe Asn Ile Arg Ile                 85  #                 90  #                 95Lys Asn Val Thr Arg Ser Asp Ala Gly Lys Ty #r Arg Cys Glu Val Ser            100       #           105       #           110Ala Pro Ser Glu Gln Gly Gln Asn Leu Glu Gl #u Asp Thr Val Thr Leu        115           #       120           #       125Glu Val Leu Val Ala Pro Ala Val Pro Ser Cy #s Glu Val Pro Ser Ser    130               #   135               #   140Ala Leu Ser Gly Thr Val Val Glu Leu Arg Cy #s Gln Asp Lys Glu Gly145                 1 #50                 1 #55                 1 #60Asn Pro Ala Pro Glu Tyr Thr Trp Phe Lys As #p Gly Ile Arg Leu Leu                165   #               170   #               175Glu Asn Pro Arg Leu Gly Ser Gln Ser Thr As #n Ser Ser Tyr Thr Met            180       #           185       #           190Asn Thr Lys Thr Gly Thr Leu Gln Phe Asn Th #r Val Ser Lys Leu Asp        195           #       200           #       205Thr Gly Glu Tyr Ser Cys Glu Ala Arg Asn Se #r Val Gly Tyr Arg Arg    210               #   215               #   220Cys Pro Gly Lys Arg Met Gln Val Asp Asp Le #u Asn Ile Ser Gly Ile225                 2 #30                 2 #35                 2 #40Ile Ala Ala Val Val Val Val Ala Leu Val Il #e Ser Val Cys Gly Leu                245   #               250   #               255Gly Val Cys Tyr Ala Gln Arg Lys Gly Tyr Ph #e Ser Lys Glu Thr Ser            260       #           265       #           270Phe Gln Lys Ser Asn Ser Ser Ser Lys Ala Th #r Thr Met Ser Glu Asn        275           #       280           #       285Val Gln Trp Leu Thr Pro Val Ile Pro Ala Le #u Trp Lys Ala Ala Ala    290               #   295               #   300Gly Gly Ser Arg Gly Gln Glu Phe 305                 3 #10<210> SEQ ID NO 65 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 65atcgttgtga agttagtgcc cc            #                  #                 22 <210> SEQ ID NO 66 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 66acctgcgata tccaacagaa ttg            #                  #                23 <210> SEQ ID NO 67 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 67ggaagaggat acagtcactc tggaagtatt agtggctcca gcagttcc  #                48 <210> SEQ ID NO 68 <211> LENGTH: 2639<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68gacatcggag gtgggctagc actgaaactg cttttcaaga cgaggaagag ga#ggagaaag     60agaaagaaga ggaagatgtt gggcaacatt tatttaacat gctccacagc cc#ggaccctg    120gcatcatgct gctattcctg caaatactga agaagcatgg gatttaaata tt#ttacttct    180aaataaatga attactcaat ctcctatgac catctataca tactccacct tc#aaaaagta    240catcaatatt atatcattaa ggaaatagta accttctctt ctccaatatg ca#tgacattt    300ttggacaatg caattgtggc actggcactt atttcagtga agaaaaactt tg#tggttcta    360tggcattcat catttgacaa atgcaagcat cttccttatc aatcagctcc ta#ttgaactt    420actagcactg actgtggaat ccttaagggc ccattacatt tctgaagaag aa#agctaaga    480tgaaggacat gccactccga attcatgtgc tacttggcct agctatcact ac#actagtac    540aagctgtaga taaaaaagtg gattgtccac ggttatgtac gtgtgaaatc ag#gccttggt    600ttacacccag atccatttat atggaagcat ctacagtgga ttgtaatgat tt#aggtcttt    660taactttccc agccagattg ccagctaaca cacagattct tctcctacag ac#taacaata    720ttgcaaaaat tgaatactcc acagactttc cagtaaacct tactggcctg ga#tttatctc    780aaaacaattt atcttcagtc accaatatta atgtaaaaaa gatgcctcag ct#cctttctg    840tgtacctaga ggaaaacaaa cttactgaac tgcctgaaaa atgtctgtcc ga#actgagca    900acttacaaga actctatatt aatcacaact tgctttctac aatttcacct gg#agccttta    960ttggcctaca taatcttctt cgacttcatc tcaattcaaa tagattgcag at#gatcaaca   1020gtaagtggtt tgatgctctt ccaaatctag agattctgat gattggggaa aa#tccaatta   1080tcagaatcaa agacatgaac tttaagcctc ttatcaatct tcgcagcctg gt#tatagctg   1140gtataaacct cacagaaata ccagataacg ccttggttgg actggaaaac tt#agaaagca   1200tctcttttta cgataacagg cttattaaag taccccatgt tgctcttcaa aa#agttgtaa   1260atctcaaatt tttggatcta aataaaaatc ctattaatag aatacgaagg gg#tgatttta   1320gcaatatgct acacttaaaa gagttgggga taaataatat gcctgagctg at#ttccatcg   1380atagtcttgc tgtggataac ctgccagatt taagaaaaat agaagctact aa#caacccta   1440gattgtctta cattcacccc aatgcatttt tcagactccc caagctggaa tc#actcatgc   1500tgaacagcaa tgctctcagt gccctgtacc atggtaccat tgagtctctg cc#aaacctca   1560aggaaatcag catacacagt aaccccatca ggtgtgactg tgtcatccgt tg#gatgaaca   1620tgaacaaaac caacattcga ttcatggagc cagattcact gttttgcgtg ga#cccacctg   1680aattccaagg tcagaatgtt cggcaagtgc atttcaggga catgatggaa at#ttgtctcc   1740ctcttatagc tcctgagagc tttccttcta atctaaatgt agaagctggg ag#ctatgttt   1800cctttcactg tagagctact gcagaaccac agcctgaaat ctactggata ac#accttctg   1860gtcaaaaact cttgcctaat accctgacag acaagttcta tgtccattct ga#gggaacac   1920tagatataaa tggcgtaact cccaaagaag ggggtttata tacttgtata gc#aactaacc   1980tagttggcgc tgacttgaag tctgttatga tcaaagtgga tggatctttt cc#acaagata   2040acaatggctc tttgaatatt aaaataagag atattcaggc caattcagtt tt#ggtgtcct   2100ggaaagcaag ttctaaaatt ctcaaatcta gtgttaaatg gacagccttt gt#caagactg   2160aaaattctca tgctgcgcaa agtgctcgaa taccatctga tgtcaaggta ta#taatctta   2220ctcatctgaa tccatcaact gagtataaaa tttgtattga tattcccacc at#ctatcaga   2280aaaacagaaa aaaatgtgta aatgtcacca ccaaaggttt gcaccctgat ca#aaaagagt   2340atgaaaagaa taataccaca acacttatgg cctgtcttgg aggccttctg gg#gattattg   2400gtgtgatatg tcttatcagc tgcctctctc cagaaatgaa ctgtgatggt gg#acacagct   2460atgtgaggaa ttacttacag aaaccaacct ttgcattagg tgagctttat cc#tcctctga   2520taaatctctg ggaagcagga aaagaaaaaa gtacatcact gaaagtaaaa gc#aactgtta   2580taggtttacc aacaaatatg tcctaaaaac caccaaggaa acctactcca aa#aatgaac    2639 <210> SEQ ID NO 69 <211> LENGTH: 708 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 69Met Lys Asp Met Pro Leu Arg Ile His Val Le #u Leu Gly Leu Ala Ile  1               5  #                 10  #                 15Thr Thr Leu Val Gln Ala Val Asp Lys Lys Va #l Asp Cys Pro Arg Leu             20      #             25      #             30Cys Thr Cys Glu Ile Arg Pro Trp Phe Thr Pr #o Arg Ser Ile Tyr Met         35          #         40          #         45Glu Ala Ser Thr Val Asp Cys Asn Asp Leu Gl #y Leu Leu Thr Phe Pro     50              #     55              #     60Ala Arg Leu Pro Ala Asn Thr Gln Ile Leu Le #u Leu Gln Thr Asn Asn 65                  # 70                  # 75                  # 80Ile Ala Lys Ile Glu Tyr Ser Thr Asp Phe Pr #o Val Asn Leu Thr Gly                 85  #                 90  #                 95Leu Asp Leu Ser Gln Asn Asn Leu Ser Ser Va #l Thr Asn Ile Asn Val            100       #           105       #           110Lys Lys Met Pro Gln Leu Leu Ser Val Tyr Le #u Glu Glu Asn Lys Leu        115           #       120           #       125Thr Glu Leu Pro Glu Lys Cys Leu Ser Glu Le #u Ser Asn Leu Gln Glu    130               #   135               #   140Leu Tyr Ile Asn His Asn Leu Leu Ser Thr Il #e Ser Pro Gly Ala Phe145                 1 #50                 1 #55                 1 #60Ile Gly Leu His Asn Leu Leu Arg Leu His Le #u Asn Ser Asn Arg Leu                165   #               170   #               175Gln Met Ile Asn Ser Lys Trp Phe Asp Ala Le #u Pro Asn Leu Glu Ile            180       #           185       #           190Leu Met Ile Gly Glu Asn Pro Ile Ile Arg Il #e Lys Asp Met Asn Phe        195           #       200           #       205Lys Pro Leu Ile Asn Leu Arg Ser Leu Val Il #e Ala Gly Ile Asn Leu    210               #   215               #   220Thr Glu Ile Pro Asp Asn Ala Leu Val Gly Le #u Glu Asn Leu Glu Ser225                 2 #30                 2 #35                 2 #40Ile Ser Phe Tyr Asp Asn Arg Leu Ile Lys Va #l Pro His Val Ala Leu                245   #               250   #               255Gln Lys Val Val Asn Leu Lys Phe Leu Asp Le #u Asn Lys Asn Pro Ile            260       #           265       #           270Asn Arg Ile Arg Arg Gly Asp Phe Ser Asn Me #t Leu His Leu Lys Glu        275           #       280           #       285Leu Gly Ile Asn Asn Met Pro Glu Leu Ile Se #r Ile Asp Ser Leu Ala    290               #   295               #   300Val Asp Asn Leu Pro Asp Leu Arg Lys Ile Gl #u Ala Thr Asn Asn Pro305                 3 #10                 3 #15                 3 #20Arg Leu Ser Tyr Ile His Pro Asn Ala Phe Ph #e Arg Leu Pro Lys Leu                325   #               330   #               335Glu Ser Leu Met Leu Asn Ser Asn Ala Leu Se #r Ala Leu Tyr His Gly            340       #           345       #           350Thr Ile Glu Ser Leu Pro Asn Leu Lys Glu Il #e Ser Ile His Ser Asn        355           #       360           #       365Pro Ile Arg Cys Asp Cys Val Ile Arg Trp Me #t Asn Met Asn Lys Thr    370               #   375               #   380Asn Ile Arg Phe Met Glu Pro Asp Ser Leu Ph #e Cys Val Asp Pro Pro385                 3 #90                 3 #95                 4 #00Glu Phe Gln Gly Gln Asn Val Arg Gln Val Hi #s Phe Arg Asp Met Met                405   #               410   #               415Glu Ile Cys Leu Pro Leu Ile Ala Pro Glu Se #r Phe Pro Ser Asn Leu            420       #           425       #           430Asn Val Glu Ala Gly Ser Tyr Val Ser Phe Hi #s Cys Arg Ala Thr Ala        435           #       440           #       445Glu Pro Gln Pro Glu Ile Tyr Trp Ile Thr Pr #o Ser Gly Gln Lys Leu    450               #   455               #   460Leu Pro Asn Thr Leu Thr Asp Lys Phe Tyr Va #l His Ser Glu Gly Thr465                 4 #70                 4 #75                 4 #80Leu Asp Ile Asn Gly Val Thr Pro Lys Glu Gl #y Gly Leu Tyr Thr Cys                485   #               490   #               495Ile Ala Thr Asn Leu Val Gly Ala Asp Leu Ly #s Ser Val Met Ile Lys            500       #           505       #           510Val Asp Gly Ser Phe Pro Gln Asp Asn Asn Gl #y Ser Leu Asn Ile Lys        515           #       520           #       525Ile Arg Asp Ile Gln Ala Asn Ser Val Leu Va #l Ser Trp Lys Ala Ser    530               #   535               #   540Ser Lys Ile Leu Lys Ser Ser Val Lys Trp Th #r Ala Phe Val Lys Thr545                 5 #50                 5 #55                 5 #60Glu Asn Ser His Ala Ala Gln Ser Ala Arg Il #e Pro Ser Asp Val Lys                565   #               570   #               575Val Tyr Asn Leu Thr His Leu Asn Pro Ser Th #r Glu Tyr Lys Ile Cys            580       #           585       #           590Ile Asp Ile Pro Thr Ile Tyr Gln Lys Asn Ar #g Lys Lys Cys Val Asn        595           #       600           #       605Val Thr Thr Lys Gly Leu His Pro Asp Gln Ly #s Glu Tyr Glu Lys Asn    610               #   615               #   620Asn Thr Thr Thr Leu Met Ala Cys Leu Gly Gl #y Leu Leu Gly Ile Ile625                 6 #30                 6 #35                 6 #40Gly Val Ile Cys Leu Ile Ser Cys Leu Ser Pr #o Glu Met Asn Cys Asp                645   #               650   #               655Gly Gly His Ser Tyr Val Arg Asn Tyr Leu Gl #n Lys Pro Thr Phe Ala            660       #           665       #           670Leu Gly Glu Leu Tyr Pro Pro Leu Ile Asn Le #u Trp Glu Ala Gly Lys        675           #       680           #       685Glu Lys Ser Thr Ser Leu Lys Val Lys Ala Th #r Val Ile Gly Leu Pro    690               #   695               #   700 Thr Asn Met Ser 705<210> SEQ ID NO 70 <211> LENGTH: 1305 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 70gcccgggact ggcgcaaggt gcccaagcaa ggaaagaaat aatgaagaga ca#catgtgtt     60agctgcagcc ttttgaaaca cgcaagaagg aaatcaatag tgtggacagg gc#tggaacct    120ttaccacgct tgttggagta gatgaggaat gggctcgtga ttatgctgac at#tccagcat    180gaatctggta gacctgtggt taacccgttc cctctccatg tgtctcctcc ta#caaagttt    240tgttcttatg atactgtgct ttcattctgc cagtatgtgt cccaagggct gt#ctttgttc    300ttcctctggg ggtttaaatg tcacctgtag caatgcaaat ctcaaggaaa ta#cctagaga    360tcttcctcct gaaacagtct tactgtatct ggactccaat cagatcacat ct#attcccaa    420tgaaattttt aaggacctcc atcaactgag agttctcaac ctgtccaaaa at#ggcattga    480gtttatcgat gagcatgcct tcaaaggagt agctgaaacc ttgcagactc tg#gacttgtc    540cgacaatcgg attcaaagtg tgcacaaaaa tgccttcaat aacctgaagg cc#agggccag    600aattgccaac aacccctggc actgcgactg tactctacag caagttctga gg#agcatggc    660gtccaatcat gagacagccc acaacgtgat ctgtaaaacg tccgtgttgg at#gaacatgc    720tggcagacca ttcctcaatg ctgccaacga cgctgacctt tgtaacctcc ct#aaaaaaac    780taccgattat gccatgctgg tcaccatgtt tggctggttc actatggtga tc#tcatatgt    840ggtatattat gtgaggcaaa atcaggagga tgcccggaga cacctcgaat ac#ttgaaatc    900cctgccaagc aggcagaaga aagcagatga acctgatgat attagcactg tg#gtatagtg    960tccaaactga ctgtcattga gaaagaaaga aagtagtttg cgattgcagt ag#aaataagt   1020ggtttacttc tcccatccat tgtaaacatt tgaaactttg tatttcagtt tt#ttttgaat   1080tatgccactg ctgaactttt aacaaacact acaacataaa taatttgagt tt#aggtgatc   1140caccccttaa ttgtaccccc gatggtatat ttctgagtaa gctactatct ga#acattagt   1200tagatccatc tcactattta ataatgaaat ttattttttt aatttaaaag ca#aataaaag   1260 cttaactttg aaccatggga aaaaaaaaaa aaaaaaaaaa aaaca   #                1305 <210> SEQ ID NO 71 <211> LENGTH: 259<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71Met Asn Leu Val Asp Leu Trp Leu Thr Arg Se #r Leu Ser Met Cys Leu  1               5  #                 10  #                 15Leu Leu Gln Ser Phe Val Leu Met Ile Leu Cy #s Phe His Ser Ala Ser             20      #             25      #             30Met Cys Pro Lys Gly Cys Leu Cys Ser Ser Se #r Gly Gly Leu Asn Val         35          #         40          #         45Thr Cys Ser Asn Ala Asn Leu Lys Glu Ile Pr #o Arg Asp Leu Pro Pro     50              #     55              #     60Glu Thr Val Leu Leu Tyr Leu Asp Ser Asn Gl #n Ile Thr Ser Ile Pro 65                  # 70                  # 75                  # 80Asn Glu Ile Phe Lys Asp Leu His Gln Leu Ar #g Val Leu Asn Leu Ser                 85  #                 90  #                 95Lys Asn Gly Ile Glu Phe Ile Asp Glu His Al #a Phe Lys Gly Val Ala            100       #           105       #           110Glu Thr Leu Gln Thr Leu Asp Leu Ser Asp As #n Arg Ile Gln Ser Val        115           #       120           #       125His Lys Asn Ala Phe Asn Asn Leu Lys Ala Ar #g Ala Arg Ile Ala Asn    130               #   135               #   140Asn Pro Trp His Cys Asp Cys Thr Leu Gln Gl #n Val Leu Arg Ser Met145                 1 #50                 1 #55                 1 #60Ala Ser Asn His Glu Thr Ala His Asn Val Il #e Cys Lys Thr Ser Val                165   #               170   #               175Leu Asp Glu His Ala Gly Arg Pro Phe Leu As #n Ala Ala Asn Asp Ala            180       #           185       #           190Asp Leu Cys Asn Leu Pro Lys Lys Thr Thr As #p Tyr Ala Met Leu Val        195           #       200           #       205Thr Met Phe Gly Trp Phe Thr Met Val Ile Se #r Tyr Val Val Tyr Tyr    210               #   215               #   220Val Arg Gln Asn Gln Glu Asp Ala Arg Arg Hi #s Leu Glu Tyr Leu Lys225                 2 #30                 2 #35                 2 #40Ser Leu Pro Ser Arg Gln Lys Lys Ala Asp Gl #u Pro Asp Asp Ile Ser                245   #               250   #               255Thr Val Val <210> SEQ ID NO 72 <211> LENGTH: 2290 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 72accgagccga gcggaccgaa ggcgcgcccg agatgcaggt gagcaagagg at#gctggcgg     60ggggcgtgag gagcatgccc agccccctcc tggcctgctg gcagcccatc ct#cctgctgg    120tgctgggctc agtgctgtca ggctcggcca cgggctgccc gccccgctgc ga#gtgctccg    180cccaggaccg cgctgtgctg tgccaccgca agtgctttgt ggcagtcccc ga#gggcatcc    240ccaccgagac gcgcctgctg gacctaggca agaaccgcat caaaacgctc aa#ccaggacg    300agttcgccag cttcccgcac ctggaggagc tggagctcaa cgagaacatc gt#gagcgccg    360tggagcccgg cgccttcaac aacctcttca acctccggac gctgggtctc cg#cagcaacc    420gcctgaagct catcccgcta ggcgtcttca ctggcctcag caacctgacc aa#gcaggaca    480tcagcgagaa caagatcgtt atcctactgg actacatgtt tcaggacctg ta#caacctca    540agtcactgga ggttggcgac aatgacctcg tctacatctc tcaccgcgcc tt#cagcggcc    600tcaacagcct ggagcagctg acgctggaga aatgcaacct gacctccatc cc#caccgagg    660cgctgtccca cctgcacggc ctcatcgtcc tgaggctccg gcacctcaac at#caatgcca    720tccgggacta ctccttcaag aggctgtacc gactcaaggt cttggagatc tc#ccactggc    780cctacttgga caccatgaca cccaactgcc tctacggcct caacctgacg tc#cctgtcca    840tcacacactg caatctgacc gctgtgccct acctggccgt ccgccaccta gt#ctatctcc    900gcttcctcaa cctctcctac aaccccatca gcaccattga gggctccatg tt#gcatgagc    960tgctccggct gcaggagatc cagctggtgg gcgggcagct ggccgtggtg ga#gccctatg   1020ccttccgcgg cctcaactac ctgcgcgtgc tcaatgtctc tggcaaccag ct#gaccacac   1080tggaggaatc agtcttccac tcggtgggca acctggagac actcatcctg ga#ctccaacc   1140cgctggcctg cgactgtcgg ctcctgtggg tgttccggcg ccgctggcgg ct#caacttca   1200accggcagca gcccacgtgc gccacgcccg agtttgtcca gggcaaggag tt#caaggact   1260tccctgatgt gctactgccc aactacttca cctgccgccg cgcccgcatc cg#ggaccgca   1320aggcccagca ggtgtttgtg gacgagggcc acacggtgca gtttgtgtgc cg#ggccgatg   1380gcgacccgcc gcccgccatc ctctggctct caccccgaaa gcacctggtc tc#agccaaga   1440gcaatgggcg gctcacagtc ttccctgatg gcacgctgga ggtgcgctac gc#ccaggtac   1500aggacaacgg cacgtacctg tgcatcgcgg ccaacgcggg cggcaacgac tc#catgcccg   1560cccacctgca tgtgcgcagc tactcgcccg actggcccca tcagcccaac aa#gaccttcg   1620ctttcatctc caaccagccg ggcgagggag aggccaacag cacccgcgcc ac#tgtgcctt   1680tccccttcga catcaagacc ctcatcatcg ccaccaccat gggcttcatc tc#tttcctgg   1740gcgtcgtcct cttctgcctg gtgctgctgt ttctctggag ccggggcaag gg#caacacaa   1800agcacaacat cgagatcgag tatgtgcccc gaaagtcgga cgcaggcatc ag#ctccgccg   1860acgcgccccg caagttcaac atgaagatga tatgaggccg gggcgggggg ca#gggacccc   1920cgggcggccg ggcaggggaa ggggcctggt cgccacctgc tcactctcca gt#ccttccca   1980cctcctccct acccttctac acacgttctc tttctccctc ccgcctccgt cc#cctgctgc   2040cccccgccag ccctcaccac ctgccctcct tctaccagga cctcagaagc cc#agacctgg   2100ggaccccacc tacacagggg cattgacaga ctggagttga aagccgacga ac#cgacacgc   2160ggcagagtca ataattcaat aaaaaagtta cgaactttct ctgtaacttg gg#tttcaata   2220attatggatt tttatgaaaa cttgaaataa taaaaagaga aaaaaactaa aa#aaaaaaaa   2280 aaaaaaaaaa                 #                  #                   #      2290 <210> SEQ ID NO 73 <211> LENGTH: 620<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 73Met Gln Val Ser Lys Arg Met Leu Ala Gly Gl #y Val Arg Ser Met Pro  1               5  #                 10  #                 15Ser Pro Leu Leu Ala Cys Trp Gln Pro Ile Le #u Leu Leu Val Leu Gly             20      #             25      #             30Ser Val Leu Ser Gly Ser Ala Thr Gly Cys Pr #o Pro Arg Cys Glu Cys         35          #         40          #         45Ser Ala Gln Asp Arg Ala Val Leu Cys His Ar #g Lys Cys Phe Val Ala     50              #     55              #     60Val Pro Glu Gly Ile Pro Thr Glu Thr Arg Le #u Leu Asp Leu Gly Lys 65                  # 70                  # 75                  # 80Asn Arg Ile Lys Thr Leu Asn Gln Asp Glu Ph #e Ala Ser Phe Pro His                 85  #                 90  #                 95Leu Glu Glu Leu Glu Leu Asn Glu Asn Ile Va #l Ser Ala Val Glu Pro            100       #           105       #           110Gly Ala Phe Asn Asn Leu Phe Asn Leu Arg Th #r Leu Gly Leu Arg Ser        115           #       120           #       125Asn Arg Leu Lys Leu Ile Pro Leu Gly Val Ph #e Thr Gly Leu Ser Asn    130               #   135               #   140Leu Thr Lys Gln Asp Ile Ser Glu Asn Lys Il #e Val Ile Leu Leu Asp145                 1 #50                 1 #55                 1 #60Tyr Met Phe Gln Asp Leu Tyr Asn Leu Lys Se #r Leu Glu Val Gly Asp                165   #               170   #               175Asn Asp Leu Val Tyr Ile Ser His Arg Ala Ph #e Ser Gly Leu Asn Ser            180       #           185       #           190Leu Glu Gln Leu Thr Leu Glu Lys Cys Asn Le #u Thr Ser Ile Pro Thr        195           #       200           #       205Glu Ala Leu Ser His Leu His Gly Leu Ile Va #l Leu Arg Leu Arg His    210               #   215               #   220Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Ph #e Lys Arg Leu Tyr Arg225                 2 #30                 2 #35                 2 #40Leu Lys Val Leu Glu Ile Ser His Trp Pro Ty #r Leu Asp Thr Met Thr                245   #               250   #               255Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr Se #r Leu Ser Ile Thr His            260       #           265       #           270Cys Asn Leu Thr Ala Val Pro Tyr Leu Ala Va #l Arg His Leu Val Tyr        275           #       280           #       285Leu Arg Phe Leu Asn Leu Ser Tyr Asn Pro Il #e Ser Thr Ile Glu Gly    290               #   295               #   300Ser Met Leu His Glu Leu Leu Arg Leu Gln Gl #u Ile Gln Leu Val Gly305                 3 #10                 3 #15                 3 #20Gly Gln Leu Ala Val Val Glu Pro Tyr Ala Ph #e Arg Gly Leu Asn Tyr                325   #               330   #               335Leu Arg Val Leu Asn Val Ser Gly Asn Gln Le #u Thr Thr Leu Glu Glu            340       #           345       #           350Ser Val Phe His Ser Val Gly Asn Leu Glu Th #r Leu Ile Leu Asp Ser        355           #       360           #       365Asn Pro Leu Ala Cys Asp Cys Arg Leu Leu Tr #p Val Phe Arg Arg Arg    370               #   375               #   380Trp Arg Leu Asn Phe Asn Arg Gln Gln Pro Th #r Cys Ala Thr Pro Glu385                 3 #90                 3 #95                 4 #00Phe Val Gln Gly Lys Glu Phe Lys Asp Phe Pr #o Asp Val Leu Leu Pro                405   #               410   #               415Asn Tyr Phe Thr Cys Arg Arg Ala Arg Ile Ar #g Asp Arg Lys Ala Gln            420       #           425       #           430Gln Val Phe Val Asp Glu Gly His Thr Val Gl #n Phe Val Cys Arg Ala        435           #       440           #       445Asp Gly Asp Pro Pro Pro Ala Ile Leu Trp Le #u Ser Pro Arg Lys His    450               #   455               #   460Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Th #r Val Phe Pro Asp Gly465                 4 #70                 4 #75                 4 #80Thr Leu Glu Val Arg Tyr Ala Gln Val Gln As #p Asn Gly Thr Tyr Leu                485   #               490   #               495Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Se #r Met Pro Ala His Leu            500       #           505       #           510His Val Arg Ser Tyr Ser Pro Asp Trp Pro Hi #s Gln Pro Asn Lys Thr        515           #       520           #       525Phe Ala Phe Ile Ser Asn Gln Pro Gly Glu Gl #y Glu Ala Asn Ser Thr    530               #   535               #   540Arg Ala Thr Val Pro Phe Pro Phe Asp Ile Ly #s Thr Leu Ile Ile Ala545                 5 #50                 5 #55                 5 #60Thr Thr Met Gly Phe Ile Ser Phe Leu Gly Va #l Val Leu Phe Cys Leu                565   #               570   #               575Val Leu Leu Phe Leu Trp Ser Arg Gly Lys Gl #y Asn Thr Lys His Asn            580       #           585       #           590Ile Glu Ile Glu Tyr Val Pro Arg Lys Ser As #p Ala Gly Ile Ser Ser        595           #       600           #       605Ala Asp Ala Pro Arg Lys Phe Asn Met Lys Me #t Ile     610              #   615               #   620 <210> SEQ ID NO 74 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 74tcacctggag cctttattgg cc            #                  #                 22 <210> SEQ ID NO 75 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 75ataccagcta taaccaggct gcg            #                  #                23 <210> SEQ ID NO 76 <211> LENGTH: 52 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 76caacagtaag tggtttgatg ctcttccaaa tctagagatt ctgatgattg  #              50 gg                   #                  #                   #              52 <210> SEQ ID NO 77<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 77ccatgtgtct cctcctacaa ag            #                  #                 22 <210> SEQ ID NO 78 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 78gggaatagat gtgatctgat tgg            #                  #                23 <210> SEQ ID NO 79 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 79cacctgtagc aatgcaaatc tcaaggaaat acctagagat cttcctcctg  #              50 <210> SEQ ID NO 80 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 80agcaaccgcc tgaagctcat cc            #                  #                 22 <210> SEQ ID NO 81 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 81aaggcgcggt gaaagatgta gacg           #                  #                24 <210> SEQ ID NO 82 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 82gactacatgt ttcaggacct gtacaacctc aagtcactgg aggttggcga  #              50 <210> SEQ ID NO 83 <211> LENGTH: 1685 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 83cccacgcgtc cgcacctcgg ccccgggctc cgaagcggct cgggggcgcc ct#ttcggtca     60acatcgtagt ccaccccctc cccatcccca gcccccgggg attcaggctc gc#cagcgccc    120agccagggag ccggccggga agcgcgatgg gggccccagc cgcctcgctc ct#gctcctgc    180tcctgctgtt cgcctgctgc tgggcgcccg gcggggccaa cctctcccag ga#cgacagcc    240agccctggac atctgatgaa acagtggtgg ctggtggcac cgtggtgctc aa#gtgccaag    300tgaaagatca cgaggactca tccctgcaat ggtctaaccc tgctcagcag ac#tctctact    360ttggggagaa gagagccctt cgagataatc gaattcagct ggttacctct ac#gccccacg    420agctcagcat cagcatcagc aatgtggccc tggcagacga gggcgagtac ac#ctgctcaa    480tcttcactat gcctgtgcga actgccaagt ccctcgtcac tgtgctagga at#tccacaga    540agcccatcat cactggttat aaatcttcat tacgggaaaa agacacagcc ac#cctaaact    600gtcagtcttc tgggagcaag cctgcagccc ggctcacctg gagaaagggt ga#ccaagaac    660tccacggaga accaacccgc atacaggaag atcccaatgg taaaaccttc ac#tgtcagca    720gctcggtgac attccaggtt acccgggagg atgatggggc gagcatcgtg tg#ctctgtga    780accatgaatc tctaaaggga gctgacagat ccacctctca acgcattgaa gt#tttataca    840caccaactgc gatgattagg ccagaccctc cccatcctcg tgagggccag aa#gctgttgc    900tacactgtga gggtcgcggc aatccagtcc cccagcagta cctatgggag aa#ggagggca    960gtgtgccacc cctgaagatg acccaggaga gtgccctgat cttccctttc ct#caacaaga   1020gtgacagtgg cacctacggc tgcacagcca ccagcaacat gggcagctac aa#ggcctact   1080acaccctcaa tgttaatgac cccagtccgg tgccctcctc ctccagcacc ta#ccacgcca   1140tcatcggtgg gatcgtggct ttcattgtct tcctgctgct catcatgctc at#cttccttg   1200gccactactt gatccggcac aaaggaacct acctgacaca tgaggcaaaa gg#ctccgacg   1260atgctccaga cgcggacacg gccatcatca atgcagaagg cgggcagtca gg#aggggacg   1320acaagaagga atatttcatc tagaggcgcc tgcccacttc ctgcgccccc ca#ggggccct   1380gtggggactg ctggggccgt caccaacccg gacttgtaca gagcaaccgc ag#ggccgccc   1440ctcccgcttg ctccccagcc cacccacccc cctgtacaga atgtctgctt tg#ggtgcggt   1500tttgtactcg gtttggaatg gggagggagg agggcggggg gaggggaggg tt#gccctcag   1560ccctttccgt ggcttctctg catttgggtt attattattt ttgtaacaat cc#caaatcaa   1620atctgtctcc aggctggaga ggcaggagcc ctggggtgag aaaagcaaaa aa#caaacaaa   1680 aaaca                  #                  #                   #          1685 <210> SEQ ID NO 84 <211> LENGTH: 398<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 84Met Gly Ala Pro Ala Ala Ser Leu Leu Leu Le #u Leu Leu Leu Phe Ala  1               5  #                 10  #                 15Cys Cys Trp Ala Pro Gly Gly Ala Asn Leu Se #r Gln Asp Asp Ser Gln             20      #             25      #             30Pro Trp Thr Ser Asp Glu Thr Val Val Ala Gl #y Gly Thr Val Val Leu         35          #         40          #         45Lys Cys Gln Val Lys Asp His Glu Asp Ser Se #r Leu Gln Trp Ser Asn     50              #     55              #     60Pro Ala Gln Gln Thr Leu Tyr Phe Gly Glu Ly #s Arg Ala Leu Arg Asp 65                  # 70                  # 75                  # 80Asn Arg Ile Gln Leu Val Thr Ser Thr Pro Hi #s Glu Leu Ser Ile Ser                 85  #                 90  #                 95Ile Ser Asn Val Ala Leu Ala Asp Glu Gly Gl #u Tyr Thr Cys Ser Ile            100       #           105       #           110Phe Thr Met Pro Val Arg Thr Ala Lys Ser Le #u Val Thr Val Leu Gly        115           #       120           #       125Ile Pro Gln Lys Pro Ile Ile Thr Gly Tyr Ly #s Ser Ser Leu Arg Glu    130               #   135               #   140Lys Asp Thr Ala Thr Leu Asn Cys Gln Ser Se #r Gly Ser Lys Pro Ala145                 1 #50                 1 #55                 1 #60Ala Arg Leu Thr Trp Arg Lys Gly Asp Gln Gl #u Leu His Gly Glu Pro                165   #               170   #               175Thr Arg Ile Gln Glu Asp Pro Asn Gly Lys Th #r Phe Thr Val Ser Ser            180       #           185       #           190Ser Val Thr Phe Gln Val Thr Arg Glu Asp As #p Gly Ala Ser Ile Val        195           #       200           #       205Cys Ser Val Asn His Glu Ser Leu Lys Gly Al #a Asp Arg Ser Thr Ser    210               #   215               #   220Gln Arg Ile Glu Val Leu Tyr Thr Pro Thr Al #a Met Ile Arg Pro Asp225                 2 #30                 2 #35                 2 #40Pro Pro His Pro Arg Glu Gly Gln Lys Leu Le #u Leu His Cys Glu Gly                245   #               250   #               255Arg Gly Asn Pro Val Pro Gln Gln Tyr Leu Tr #p Glu Lys Glu Gly Ser            260       #           265       #           270Val Pro Pro Leu Lys Met Thr Gln Glu Ser Al #a Leu Ile Phe Pro Phe        275           #       280           #       285Leu Asn Lys Ser Asp Ser Gly Thr Tyr Gly Cy #s Thr Ala Thr Ser Asn    290               #   295               #   300Met Gly Ser Tyr Lys Ala Tyr Tyr Thr Leu As #n Val Asn Asp Pro Ser305                 3 #10                 3 #15                 3 #20Pro Val Pro Ser Ser Ser Ser Thr Tyr His Al #a Ile Ile Gly Gly Ile                325   #               330   #               335Val Ala Phe Ile Val Phe Leu Leu Leu Ile Me #t Leu Ile Phe Leu Gly            340       #           345       #           350His Tyr Leu Ile Arg His Lys Gly Thr Tyr Le #u Thr His Glu Ala Lys        355           #       360           #       365Gly Ser Asp Asp Ala Pro Asp Ala Asp Thr Al #a Ile Ile Asn Ala Glu    370               #   375               #   380Gly Gly Gln Ser Gly Gly Asp Asp Lys Lys Gl #u Tyr Phe Ile385                 3 #90                 3 #95 <210> SEQ ID NO 85<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 85gctaggaatt ccacagaagc cc            #                  #                 22 <210> SEQ ID NO 86 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 86aacctggaat gtcaccgagc tg            #                  #                 22 <210> SEQ ID NO 87 <211> LENGTH: 26 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 87cctagcacag tgacgaggga cttggc           #                  #              26 <210> SEQ ID NO 88 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 88aagacacagc caccctaaac tgtcagtctt ctgggagcaa gcctgcagcc  #              50 <210> SEQ ID NO 89 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 89gccctggcag acgagggcga gtacacctgc tcaatcttca ctatgcctgt  #              50 <210> SEQ ID NO 90 <211> LENGTH: 2755 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 90gggggttagg gaggaaggaa tccaccccca cccccccaaa cccttttctt ct#cctttcct     60ggcttcggac attggagcac taaatgaact tgaattgtgt ctgtggcgag ca#ggatggtc    120gctgttactt tgtgatgaga tcggggatga attgctcgct ttaaaaatgc tg#ctttggat    180tctgttgctg gagacgtctc tttgttttgc cgctggaaac gttacagggg ac#gtttgcaa    240agagaagatc tgttcctgca atgagataga aggggaccta cacgtagact gt#gaaaaaaa    300gggcttcaca agtctgcagc gtttcactgc cccgacttcc cagttttacc at#ttatttct    360gcatggcaat tccctcactc gacttttccc taatgagttc gctaactttt at#aatgcggt    420tagtttgcac atggaaaaca atggcttgca tgaaatcgtt ccgggggctt tt#ctggggct    480gcagctggtg aaaaggctgc acatcaacaa caacaagatc aagtcttttc ga#aagcagac    540ttttctgggg ctggacgatc tggaatatct ccaggctgat tttaatttat ta#cgagatat    600agacccgggg gccttccagg acttgaacaa gctggaggtg ctcattttaa at#gacaatct    660catcagcacc ctacctgcca acgtgttcca gtatgtgccc atcacccacc tc#gacctccg    720gggtaacagg ctgaaaacgc tgccctatga ggaggtcttg gagcaaatcc ct#ggtattgc    780ggagatcctg ctagaggata acccttggga ctgcacctgt gatctgctct cc#ctgaaaga    840atggctggaa aacattccca agaatgccct gatcggccga gtggtctgcg aa#gcccccac    900cagactgcag ggtaaagacc tcaatgaaac caccgaacag gacttgtgtc ct#ttgaaaaa    960ccgagtggat tctagtctcc cggcgccccc tgcccaagaa gagacctttg ct#cctggacc   1020cctgccaact cctttcaaga caaatgggca agaggatcat gccacaccag gg#tctgctcc   1080aaacggaggt acaaagatcc caggcaactg gcagatcaaa atcagaccca ca#gcagcgat   1140agcgacgggt agctccagga acaaaccctt agctaacagt ttaccctgcc ct#gggggctg   1200cagctgcgac cacatcccag ggtcgggttt aaagatgaac tgcaacaaca gg#aacgtgag   1260cagcttggct gatttgaagc ccaagctctc taacgtgcag gagcttttcc ta#cgagataa   1320caagatccac agcatccgaa aatcgcactt tgtggattac aagaacctca tt#ctgttgga   1380tctgggcaac aataacatcg ctactgtaga gaacaacact ttcaagaacc tt#ttggacct   1440caggtggcta tacatggata gcaattacct ggacacgctg tcccgggaga aa#ttcgcggg   1500gctgcaaaac ctagagtacc tgaacgtgga gtacaacgct atccagctca tc#ctcccggg   1560cactttcaat gccatgccca aactgaggat cctcattctc aacaacaacc tg#ctgaggtc   1620cctgcctgtg gacgtgttcg ctggggtctc gctctctaaa ctcagcctgc ac#aacaatta   1680cttcatgtac ctcccggtgg caggggtgct ggaccagtta acctccatca tc#cagataga   1740cctccacgga aacccctggg agtgctcctg cacaattgtg cctttcaagc ag#tgggcaga   1800acgcttgggt tccgaagtgc tgatgagcga cctcaagtgt gagacgccgg tg#aacttctt   1860tagaaaggat ttcatgctcc tctccaatga cgagatctgc cctcagctgt ac#gctaggat   1920ctcgcccacg ttaacttcgc acagtaaaaa cagcactggg ttggcggaga cc#gggacgca   1980ctccaactcc tacctagaca ccagcagggt gtccatctcg gtgttggtcc cg#ggactgct   2040gctggtgttt gtcacctccg ccttcaccgt ggtgggcatg ctcgtgttta tc#ctgaggaa   2100ccgaaagcgg tccaagagac gagatgccaa ctcctccgcg tccgagatta at#tccctaca   2160gacagtctgt gactcttcct actggcacaa tgggccttac aacgcagatg gg#gcccacag   2220agtgtatgac tgtggctctc actcgctctc agactaagac cccaacccca at#aggggagg   2280gcagagggaa ggcgatacat ccttccccac cgcaggcacc ccgggggctg ga#ggggcgtg   2340tacccaaatc cccgcgccat cagcctggat gggcataagt agataaataa ct#gtgagctc   2400gcacaaccga aagggcctga ccccttactt agctccctcc ttgaaacaaa ga#gcagactg   2460tggagagctg ggagagcgca gccagctcgc tctttgctga gagccccttt tg#acagaaag   2520cccagcacga ccctgctgga agaactgaca gtgccctcgc cctcggcccc gg#ggcctgtg   2580gggttggatg ccgcggttct atacatatat acatatatcc acatctatat ag#agagatag   2640atatctattt ttcccctgtg gattagcccc gtgatggctc cctgttggct ac#gcagggat   2700gggcagttgc acgaaggcat gaatgtattg taaataagta actttgactt ct#gac        2755 <210> SEQ ID NO 91 <211> LENGTH: 696 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 91Met Leu Leu Trp Ile Leu Leu Leu Glu Thr Se #r Leu Cys Phe Ala Ala  1               5  #                 10  #                 15Gly Asn Val Thr Gly Asp Val Cys Lys Glu Ly #s Ile Cys Ser Cys Asn             20      #             25      #             30Glu Ile Glu Gly Asp Leu His Val Asp Cys Gl #u Lys Lys Gly Phe Thr         35          #         40          #         45Ser Leu Gln Arg Phe Thr Ala Pro Thr Ser Gl #n Phe Tyr His Leu Phe     50              #     55              #     60Leu His Gly Asn Ser Leu Thr Arg Leu Phe Pr #o Asn Glu Phe Ala Asn 65                  # 70                  # 75                  # 80Phe Tyr Asn Ala Val Ser Leu His Met Glu As #n Asn Gly Leu His Glu                 85  #                 90  #                 95Ile Val Pro Gly Ala Phe Leu Gly Leu Gln Le #u Val Lys Arg Leu His            100       #           105       #           110Ile Asn Asn Asn Lys Ile Lys Ser Phe Arg Ly #s Gln Thr Phe Leu Gly        115           #       120           #       125Leu Asp Asp Leu Glu Tyr Leu Gln Ala Asp Ph #e Asn Leu Leu Arg Asp    130               #   135               #   140Ile Asp Pro Gly Ala Phe Gln Asp Leu Asn Ly #s Leu Glu Val Leu Ile145                 1 #50                 1 #55                 1 #60Leu Asn Asp Asn Leu Ile Ser Thr Leu Pro Al #a Asn Val Phe Gln Tyr                165   #               170   #               175Val Pro Ile Thr His Leu Asp Leu Arg Gly As #n Arg Leu Lys Thr Leu            180       #           185       #           190Pro Tyr Glu Glu Val Leu Glu Gln Ile Pro Gl #y Ile Ala Glu Ile Leu        195           #       200           #       205Leu Glu Asp Asn Pro Trp Asp Cys Thr Cys As #p Leu Leu Ser Leu Lys    210               #   215               #   220Glu Trp Leu Glu Asn Ile Pro Lys Asn Ala Le #u Ile Gly Arg Val Val225                 2 #30                 2 #35                 2 #40Cys Glu Ala Pro Thr Arg Leu Gln Gly Lys As #p Leu Asn Glu Thr Thr                245   #               250   #               255Glu Gln Asp Leu Cys Pro Leu Lys Asn Arg Va #l Asp Ser Ser Leu Pro            260       #           265       #           270Ala Pro Pro Ala Gln Glu Glu Thr Phe Ala Pr #o Gly Pro Leu Pro Thr        275           #       280           #       285Pro Phe Lys Thr Asn Gly Gln Glu Asp His Al #a Thr Pro Gly Ser Ala    290               #   295               #   300Pro Asn Gly Gly Thr Lys Ile Pro Gly Asn Tr #p Gln Ile Lys Ile Arg305                 3 #10                 3 #15                 3 #20Pro Thr Ala Ala Ile Ala Thr Gly Ser Ser Ar #g Asn Lys Pro Leu Ala                325   #               330   #               335Asn Ser Leu Pro Cys Pro Gly Gly Cys Ser Cy #s Asp His Ile Pro Gly            340       #           345       #           350Ser Gly Leu Lys Met Asn Cys Asn Asn Arg As #n Val Ser Ser Leu Ala        355           #       360           #       365Asp Leu Lys Pro Lys Leu Ser Asn Val Gln Gl #u Leu Phe Leu Arg Asp    370               #   375               #   380Asn Lys Ile His Ser Ile Arg Lys Ser His Ph #e Val Asp Tyr Lys Asn385                 3 #90                 3 #95                 4 #00Leu Ile Leu Leu Asp Leu Gly Asn Asn Asn Il #e Ala Thr Val Glu Asn                405   #               410   #               415Asn Thr Phe Lys Asn Leu Leu Asp Leu Arg Tr #p Leu Tyr Met Asp Ser            420       #           425       #           430Asn Tyr Leu Asp Thr Leu Ser Arg Glu Lys Ph #e Ala Gly Leu Gln Asn        435           #       440           #       445Leu Glu Tyr Leu Asn Val Glu Tyr Asn Ala Il #e Gln Leu Ile Leu Pro    450               #   455               #   460Gly Thr Phe Asn Ala Met Pro Lys Leu Arg Il #e Leu Ile Leu Asn Asn465                 4 #70                 4 #75                 4 #80Asn Leu Leu Arg Ser Leu Pro Val Asp Val Ph #e Ala Gly Val Ser Leu                485   #               490   #               495Ser Lys Leu Ser Leu His Asn Asn Tyr Phe Me #t Tyr Leu Pro Val Ala            500       #           505       #           510Gly Val Leu Asp Gln Leu Thr Ser Ile Ile Gl #n Ile Asp Leu His Gly        515           #       520           #       525Asn Pro Trp Glu Cys Ser Cys Thr Ile Val Pr #o Phe Lys Gln Trp Ala    530               #   535               #   540Glu Arg Leu Gly Ser Glu Val Leu Met Ser As #p Leu Lys Cys Glu Thr545                 5 #50                 5 #55                 5 #60Pro Val Asn Phe Phe Arg Lys Asp Phe Met Le #u Leu Ser Asn Asp Glu                565   #               570   #               575Ile Cys Pro Gln Leu Tyr Ala Arg Ile Ser Pr #o Thr Leu Thr Ser His            580       #           585       #           590Ser Lys Asn Ser Thr Gly Leu Ala Glu Thr Gl #y Thr His Ser Asn Ser        595           #       600           #       605Tyr Leu Asp Thr Ser Arg Val Ser Ile Ser Va #l Leu Val Pro Gly Leu    610               #   615               #   620Leu Leu Val Phe Val Thr Ser Ala Phe Thr Va #l Val Gly Met Leu Val625                 6 #30                 6 #35                 6 #40Phe Ile Leu Arg Asn Arg Lys Arg Ser Lys Ar #g Arg Asp Ala Asn Ser                645   #               650   #               655Ser Ala Ser Glu Ile Asn Ser Leu Gln Thr Va #l Cys Asp Ser Ser Tyr            660       #           665       #           670Trp His Asn Gly Pro Tyr Asn Ala Asp Gly Al #a His Arg Val Tyr Asp        675           #       680           #       685Cys Gly Ser His Ser Leu Ser Asp     690               #   695<210> SEQ ID NO 92 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 92gttggatctg ggcaacaata ac            #                  #                 22 <210> SEQ ID NO 93 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 93attgttgtgc aggctgagtt taag           #                  #                24 <210> SEQ ID NO 94 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 94ggtggctata catggatagc aattacctgg acacgctgtc ccggg    #                  #45 <210> SEQ ID NO 95 <211> LENGTH: 2226 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 95agtcgactgc gtcccctgta cccggcgcca gctgtgttcc tgaccccaga at#aactcagg     60gctgcaccgg gcctggcagc gctccgcaca catttcctgt cgcggcctaa gg#gaaactgt    120tggccgctgg gcccgcgggg ggattcttgg cagttggggg gtccgtcggg ag#cgagggcg    180gaggggaagg gagggggaac cgggttgggg aagccagctg tagagggcgg tg#accgcgct    240ccagacacag ctctgcgtcc tcgagcggga cagatccaag ttgggagcag ct#ctgcgtgc    300ggggcctcag agaatgaggc cggcgttcgc cctgtgcctc ctctggcagg cg#ctctggcc    360cgggccgggc ggcggcgaac accccactgc cgaccgtgct ggctgctcgg cc#tcgggggc    420ctgctacagc ctgcaccacg ctaccatgaa gcggcaggcg gccgaggagg cc#tgcatcct    480gcgaggtggg gcgctcagca ccgtgcgtgc gggcgccgag ctgcgcgctg tg#ctcgcgct    540cctgcgggca ggcccagggc ccggaggggg ctccaaagac ctgctgttct gg#gtcgcact    600ggagcgcagg cgttcccact gcaccctgga gaacgagcct ttgcggggtt tc#tcctggct    660gtcctccgac cccggcggtc tcgaaagcga cacgctgcag tgggtggagg ag#ccccaacg    720ctcctgcacc gcgcggagat gcgcggtact ccaggccacc ggtggggtcg ag#cccgcagg    780ctggaaggag atgcgatgcc acctgcgcgc caacggctac ctgtgcaagt ac#cagtttga    840ggtcttgtgt cctgcgccgc gccccggggc cgcctctaac ttgagctatc gc#gcgccctt    900ccagctgcac agcgccgctc tggacttcag tccacctggg accgaggtga gt#gcgctctg    960ccggggacag ctcccgatct cagttacttg catcgcggac gaaatcggcg ct#cgctggga   1020caaactctcg ggcgatgtgt tgtgtccctg ccccgggagg tacctccgtg ct#ggcaaatg   1080cgcagagctc cctaactgcc tagacgactt gggaggcttt gcctgcgaat gt#gctacggg   1140cttcgagctg gggaaggacg gccgctcttg tgtgaccagt ggggaaggac ag#ccgaccct   1200tggggggacc ggggtgccca ccaggcgccc gccggccact gcaaccagcc cc#gtgccgca   1260gagaacatgg ccaatcaggg tcgacgagaa gctgggagag acaccacttg tc#cctgaaca   1320agacaattca gtaacatcta ttcctgagat tcctcgatgg ggatcacaga gc#acgatgtc   1380tacccttcaa atgtcccttc aagccgagtc aaaggccact atcaccccat ca#gggagcgt   1440gatttccaag tttaattcta cgacttcctc tgccactcct caggctttcg ac#tcctcctc   1500tgccgtggtc ttcatatttg tgagcacagc agtagtagtg ttggtgatct tg#accatgac   1560agtactgggg cttgtcaagc tctgctttca cgaaagcccc tcttcccagc ca#aggaagga   1620gtctatgggc ccgccgggcc tggagagtga tcctgagccc gctgctttgg gc#tccagttc   1680tgcacattgc acaaacaatg gggtgaaagt cggggactgt gatctgcggg ac#agagcaga   1740gggtgccttg ctggcggagt cccctcttgg ctctagtgat gcatagggaa ac#aggggaca   1800tgggcactcc tgtgaacagt ttttcacttt tgatgaaacg gggaaccaag ag#gaacttac   1860ttgtgtaact gacaatttct gcagaaatcc cccttcctct aaattccctt ta#ctccactg   1920aggagctaaa tcagaactgc acactccttc cctgatgata gaggaagtgg aa#gtgccttt   1980aggatggtga tactggggga ccgggtagtg ctggggagag atattttctt at#gtttattc   2040ggagaatttg gagaagtgat tgaacttttc aagacattgg aaacaaatag aa#cacaatat   2100aatttacatt aaaaaataat ttctaccaaa atggaaagga aatgttctat gt#tgttcagg   2160ctaggagtat attggttcga aatcccaggg aaaaaaataa aaataaaaaa tt#aaaggatt   2220 gttgat                  #                  #                   #         2226 <210> SEQ ID NO 96 <211> LENGTH: 490<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96Met Arg Pro Ala Phe Ala Leu Cys Leu Leu Tr #p Gln Ala Leu Trp Pro  1               5  #                 10  #                 15Gly Pro Gly Gly Gly Glu His Pro Thr Ala As #p Arg Ala Gly Cys Ser             20      #             25      #             30Ala Ser Gly Ala Cys Tyr Ser Leu His His Al #a Thr Met Lys Arg Gln         35          #         40          #         45Ala Ala Glu Glu Ala Cys Ile Leu Arg Gly Gl #y Ala Leu Ser Thr Val     50              #     55              #     60Arg Ala Gly Ala Glu Leu Arg Ala Val Leu Al #a Leu Leu Arg Ala Gly 65                  # 70                  # 75                  # 80Pro Gly Pro Gly Gly Gly Ser Lys Asp Leu Le #u Phe Trp Val Ala Leu                 85  #                 90  #                 95Glu Arg Arg Arg Ser His Cys Thr Leu Glu As #n Glu Pro Leu Arg Gly            100       #           105       #           110Phe Ser Trp Leu Ser Ser Asp Pro Gly Gly Le #u Glu Ser Asp Thr Leu        115           #       120           #       125Gln Trp Val Glu Glu Pro Gln Arg Ser Cys Th #r Ala Arg Arg Cys Ala    130               #   135               #   140Val Leu Gln Ala Thr Gly Gly Val Glu Pro Al #a Gly Trp Lys Glu Met145                 1 #50                 1 #55                 1 #60Arg Cys His Leu Arg Ala Asn Gly Tyr Leu Cy #s Lys Tyr Gln Phe Glu                165   #               170   #               175Val Leu Cys Pro Ala Pro Arg Pro Gly Ala Al #a Ser Asn Leu Ser Tyr            180       #           185       #           190Arg Ala Pro Phe Gln Leu His Ser Ala Ala Le #u Asp Phe Ser Pro Pro        195           #       200           #       205Gly Thr Glu Val Ser Ala Leu Cys Arg Gly Gl #n Leu Pro Ile Ser Val    210               #   215               #   220Thr Cys Ile Ala Asp Glu Ile Gly Ala Arg Tr #p Asp Lys Leu Ser Gly225                 2 #30                 2 #35                 2 #40Asp Val Leu Cys Pro Cys Pro Gly Arg Tyr Le #u Arg Ala Gly Lys Cys                245   #               250   #               255Ala Glu Leu Pro Asn Cys Leu Asp Asp Leu Gl #y Gly Phe Ala Cys Glu            260       #           265       #           270Cys Ala Thr Gly Phe Glu Leu Gly Lys Asp Gl #y Arg Ser Cys Val Thr        275           #       280           #       285Ser Gly Glu Gly Gln Pro Thr Leu Gly Gly Th #r Gly Val Pro Thr Arg    290               #   295               #   300Arg Pro Pro Ala Thr Ala Thr Ser Pro Val Pr #o Gln Arg Thr Trp Pro305                 3 #10                 3 #15                 3 #20Ile Arg Val Asp Glu Lys Leu Gly Glu Thr Pr #o Leu Val Pro Glu Gln                325   #               330   #               335Asp Asn Ser Val Thr Ser Ile Pro Glu Ile Pr #o Arg Trp Gly Ser Gln            340       #           345       #           350Ser Thr Met Ser Thr Leu Gln Met Ser Leu Gl #n Ala Glu Ser Lys Ala        355           #       360           #       365Thr Ile Thr Pro Ser Gly Ser Val Ile Ser Ly #s Phe Asn Ser Thr Thr    370               #   375               #   380Ser Ser Ala Thr Pro Gln Ala Phe Asp Ser Se #r Ser Ala Val Val Phe385                 3 #90                 3 #95                 4 #00Ile Phe Val Ser Thr Ala Val Val Val Leu Va #l Ile Leu Thr Met Thr                405   #               410   #               415Val Leu Gly Leu Val Lys Leu Cys Phe His Gl #u Ser Pro Ser Ser Gln            420       #           425       #           430Pro Arg Lys Glu Ser Met Gly Pro Pro Gly Le #u Glu Ser Asp Pro Glu        435           #       440           #       445Pro Ala Ala Leu Gly Ser Ser Ser Ala His Cy #s Thr Asn Asn Gly Val    450               #   455               #   460Lys Val Gly Asp Cys Asp Leu Arg Asp Arg Al #a Glu Gly Ala Leu Leu465                 4 #70                 4 #75                 4 #80Ala Glu Ser Pro Leu Gly Ser Ser Asp Ala                 485  #               490 <210> SEQ ID NO 97 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 97tggaaggaga tgcgatgcca cctg           #                  #                24 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 98tgaccagtgg ggaaggacag             #                  #                   # 20 <210> SEQ ID NO 99 <211> LENGTH: 20<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 99acagagcaga gggtgccttg             #                  #                   # 20 <210> SEQ ID NO 100 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 100tcagggacaa gtggtgtctc tccc           #                  #                24 <210> SEQ ID NO 101 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 101tcagggaagg agtgtgcagt tctg           #                  #                24 <210> SEQ ID NO 102 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 102acagctcccg atctcagtta cttgcatcgc ggacgaaatc ggcgctcgct  #              50 <210> SEQ ID NO 103 <211> LENGTH: 2026 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 103cggacgcgtg ggattcagca gtggcctgtg gctgccagag cagctcctca gg#ggaaacta     60agcgtcgagt cagacggcac cataatcgcc tttaaaagtg cctccgccct gc#cggccgcg    120tatcccccgg ctacctgggc cgccccgcgg cggtgcgcgc gtgagaggga gc#gcgcgggc    180agccgagcgc cggtgtgagc cagcgctgct gccagtgtga gcggcggtgt ga#gcgcggtg    240ggtgcggagg ggcgtgtgtg ccggcgcgcg cgccgtgggg tgcaaacccc ga#gcgtctac    300gctgccatga ggggcgcgaa cgcctgggcg ccactctgcc tgctgctggc tg#ccgccacc    360cagctctcgc ggcagcagtc cccagagaga cctgttttca catgtggtgg ca#ttcttact    420ggagagtctg gatttattgg cagtgaaggt tttcctggag tgtaccctcc aa#atagcaaa    480tgtacttgga aaatcacagt tcccgaagga aaagtagtcg ttctcaattt cc#gattcata    540gacctcgaga gtgacaacct gtgccgctat gactttgtgg atgtgtacaa tg#gccatgcc    600aatggccagc gcattggccg cttctgtggc actttccggc ctggagccct tg#tgtccagt    660ggcaacaaga tgatggtgca gatgatttct gatgccaaca cagctggcaa tg#gcttcatg    720gccatgttct ccgctgctga accaaacgaa agaggggatc agtattgtgg ag#gactcctt    780gacagacctt ccggctcttt taaaaccccc aactggccag accgggatta cc#ctgcagga    840gtcacttgtg tgtggcacat tgtagcccca aagaatcagc ttatagaatt aa#agtttgag    900aagtttgatg tggagcgaga taactactgc cgatatgatt atgtggctgt gt#ttaatggc    960ggggaagtca acgatgctag aagaattgga aagtattgtg gtgatagtcc ac#ctgcgcca   1020attgtgtctg agagaaatga acttcttatt cagtttttat cagacttaag tt#taactgca   1080gatgggttta ttggtcacta catattcagg ccaaaaaaac tgcctacaac ta#cagaacag   1140cctgtcacca ccacattccc tgtaaccacg ggtttaaaac ccaccgtggc ct#tgtgtcaa   1200caaaagtgta gacggacggg gactctggag ggcaattatt gttcaagtga ct#ttgtatta   1260gccggcactg ttatcacaac catcactcgc gatgggagtt tgcacgccac ag#tctcgatc   1320atcaacatct acaaagaggg aaatttggcg attcagcagg cgggcaagaa ca#tgagtgcc   1380aggctgactg tcgtctgcaa gcagtgccct ctcctcagaa gaggtctaaa tt#acattatt   1440atgggccaag taggtgaaga tgggcgaggc aaaatcatgc caaacagctt ta#tcatgatg   1500ttcaagacca agaatcagaa gctcctggat gccttaaaaa ataagcaatg tt#aacagtga   1560actgtgtcca tttaagctgt attctgccat tgcctttgaa agatctatgt tc#tctcagta   1620gaaaaaaaaa tacttataaa attacatatt ctgaaagagg attccgaaag at#gggactgg   1680ttgactcttc acatgatgga ggtatgaggc ctccgagata gctgagggaa gt#tctttgcc   1740tgctgtcaga ggagcagcta tctgattgga aacctgccga cttagtgcgg tg#ataggaag   1800ctaaaagtgt caagcgttga cagcttggaa gcgtttattt atacatctct gt#aaaaggat   1860attttagaat tgagttgtgt gaagatgtca aaaaaagatt ttagaagtgc aa#tatttata   1920gtgttatttg tttcaccttc aagcctttgc cctgaggtgt tacaatcttg tc#ttgcgttt   1980 tctaaatcaa tgcttaataa aatattttta aaggaaaaaa aaaaaa   #               2026 <210> SEQ ID NO 104 <211> LENGTH: 415<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104Met Arg Gly Ala Asn Ala Trp Ala Pro Leu Cy #s Leu Leu Leu Ala Ala  1               5  #                 10  #                 15Ala Thr Gln Leu Ser Arg Gln Gln Ser Pro Gl #u Arg Pro Val Phe Thr             20      #             25      #             30Cys Gly Gly Ile Leu Thr Gly Glu Ser Gly Ph #e Ile Gly Ser Glu Gly         35          #         40          #         45Phe Pro Gly Val Tyr Pro Pro Asn Ser Lys Cy #s Thr Trp Lys Ile Thr     50              #     55              #     60Val Pro Glu Gly Lys Val Val Val Leu Asn Ph #e Arg Phe Ile Asp Leu 65                  # 70                  # 75                  # 80Glu Ser Asp Asn Leu Cys Arg Tyr Asp Phe Va #l Asp Val Tyr Asn Gly                 85  #                 90  #                 95His Ala Asn Gly Gln Arg Ile Gly Arg Phe Cy #s Gly Thr Phe Arg Pro            100       #           105       #           110Gly Ala Leu Val Ser Ser Gly Asn Lys Met Me #t Val Gln Met Ile Ser        115           #       120           #       125Asp Ala Asn Thr Ala Gly Asn Gly Phe Met Al #a Met Phe Ser Ala Ala    130               #   135               #   140Glu Pro Asn Glu Arg Gly Asp Gln Tyr Cys Gl #y Gly Leu Leu Asp Arg145                 1 #50                 1 #55                 1 #60Pro Ser Gly Ser Phe Lys Thr Pro Asn Trp Pr #o Asp Arg Asp Tyr Pro                165   #               170   #               175Ala Gly Val Thr Cys Val Trp His Ile Val Al #a Pro Lys Asn Gln Leu            180       #           185       #           190Ile Glu Leu Lys Phe Glu Lys Phe Asp Val Gl #u Arg Asp Asn Tyr Cys        195           #       200           #       205Arg Tyr Asp Tyr Val Ala Val Phe Asn Gly Gl #y Glu Val Asn Asp Ala    210               #   215               #   220Arg Arg Ile Gly Lys Tyr Cys Gly Asp Ser Pr #o Pro Ala Pro Ile Val225                 2 #30                 2 #35                 2 #40Ser Glu Arg Asn Glu Leu Leu Ile Gln Phe Le #u Ser Asp Leu Ser Leu                245   #               250   #               255Thr Ala Asp Gly Phe Ile Gly His Tyr Ile Ph #e Arg Pro Lys Lys Leu            260       #           265       #           270Pro Thr Thr Thr Glu Gln Pro Val Thr Thr Th #r Phe Pro Val Thr Thr        275           #       280           #       285Gly Leu Lys Pro Thr Val Ala Leu Cys Gln Gl #n Lys Cys Arg Arg Thr    290               #   295               #   300Gly Thr Leu Glu Gly Asn Tyr Cys Ser Ser As #p Phe Val Leu Ala Gly305                 3 #10                 3 #15                 3 #20Thr Val Ile Thr Thr Ile Thr Arg Asp Gly Se #r Leu His Ala Thr Val                325   #               330   #               335Ser Ile Ile Asn Ile Tyr Lys Glu Gly Asn Le #u Ala Ile Gln Gln Ala            340       #           345       #           350Gly Lys Asn Met Ser Ala Arg Leu Thr Val Va #l Cys Lys Gln Cys Pro        355           #       360           #       365Leu Leu Arg Arg Gly Leu Asn Tyr Ile Ile Me #t Gly Gln Val Gly Glu    370               #   375               #   380Asp Gly Arg Gly Lys Ile Met Pro Asn Ser Ph #e Ile Met Met Phe Lys385                 3 #90                 3 #95                 4 #00Thr Lys Asn Gln Lys Leu Leu Asp Ala Leu Ly #s Asn Lys Gln Cys                405   #               410   #               415<210> SEQ ID NO 105 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 105ccgattcata gacctcgaga gt            #                  #                 22 <210> SEQ ID NO 106 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 106gtcaaggagt cctccacaat ac            #                  #                 22 <210> SEQ ID NO 107 <211> LENGTH: 45<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 107gtgtacaatg gccatgccaa tggccagcgc attggccgct tctgt    #                  #45 <210> SEQ ID NO 108 <211> LENGTH: 1838 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 108cggacgcgtg ggcggacgcg tgggcggccc acggcgcccg cgggctgggg cg#gtcgcttc     60ttccttctcc gtggcctacg agggtcccca gcctgggtaa agatggcccc at#ggcccccg    120aagggcctag tcccagctgt gctctggggc ctcagcctct tcctcaacct cc#caggacct    180atctggctcc agccctctcc acctccccag tcttctcccc cgcctcagcc cc#atccgtgt    240catacctgcc ggggactggt tgacagcttt aacaagggcc tggagagaac ca#tccgggac    300aactttggag gtggaaacac tgcctgggag gaagagaatt tgtccaaata ca#aagacagt    360gagacccgcc tggtagaggt gctggagggt gtgtgcagca agtcagactt cg#agtgccac    420cgcctgctgg agctgagtga ggagctggtg gagagctggt ggtttcacaa gc#agcaggag    480gccccggacc tcttccagtg gctgtgctca gattccctga agctctgctg cc#ccgcaggc    540accttcgggc cctcctgcct tccctgtcct gggggaacag agaggccctg cg#gtggctac    600gggcagtgtg aaggagaagg gacacgaggg ggcagcgggc actgtgactg cc#aagccggc    660tacgggggtg aggcctgtgg ccagtgtggc cttggctact ttgaggcaga ac#gcaacgcc    720agccatctgg tatgttcggc ttgttttggc ccctgtgccc gatgctcagg ac#ctgaggaa    780tcaaactgtt tgcaatgcaa gaagggctgg gccctgcatc acctcaagtg tg#tagacatt    840gatgagtgtg gcacagaggg agccaactgt ggagctgacc aattctgcgt ga#acactgag    900ggctcctatg agtgccgaga ctgtgccaag gcctgcctag gctgcatggg gg#cagggcca    960ggtcgctgta agaagtgtag ccctggctat cagcaggtgg gctccaagtg tc#tcgatgtg   1020gatgagtgtg agacagaggt gtgtccggga gagaacaagc agtgtgaaaa ca#ccgagggc   1080ggttatcgct gcatctgtgc cgagggctac aagcagatgg aaggcatctg tg#tgaaggag   1140cagatcccag agtcagcagg cttcttctca gagatgacag aagacgagtt gg#tggtgctg   1200cagcagatgt tctttggcat catcatctgt gcactggcca cgctggctgc ta#agggcgac   1260ttggtgttca ccgccatctt cattggggct gtggcggcca tgactggcta ct#ggttgtca   1320gagcgcagtg accgtgtgct ggagggcttc atcaagggca gataatcgcg gc#caccacct   1380gtaggacctc ctcccaccca cgctgccccc agagcttggg ctgccctcct gc#tggacact   1440caggacagct tggtttattt ttgagagtgg ggtaagcacc cctacctgcc tt#acagagca   1500gcccaggtac ccaggcccgg gcagacaagg cccctggggt aaaaagtagc cc#tgaaggtg   1560gataccatga gctcttcacc tggcggggac tggcaggctt cacaatgtgt ga#atttcaaa   1620agtttttcct taatggtggc tgctagagct ttggcccctg cttaggatta gg#tggtcctc   1680acaggggtgg ggccatcaca gctccctcct gccagctgca tgctgccagt tc#ctgttctg   1740tgttcaccac atccccacac cccattgcca cttatttatt catctcagga aa#taaagaaa   1800 ggtcttggaa agttaaaaaa aaaaaaaaaa aaaaaaaa      #                   #   1838 <210> SEQ ID NO 109 <211> LENGTH: 420<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 109Met Ala Pro Trp Pro Pro Lys Gly Leu Val Pr #o Ala Val Leu Trp Gly  1               5  #                 10  #                 15Leu Ser Leu Phe Leu Asn Leu Pro Gly Pro Il #e Trp Leu Gln Pro Ser             20      #             25      #             30Pro Pro Pro Gln Ser Ser Pro Pro Pro Gln Pr #o His Pro Cys His Thr         35          #         40          #         45Cys Arg Gly Leu Val Asp Ser Phe Asn Lys Gl #y Leu Glu Arg Thr Ile     50              #     55              #     60Arg Asp Asn Phe Gly Gly Gly Asn Thr Ala Tr #p Glu Glu Glu Asn Leu 65                  # 70                  # 75                  # 80Ser Lys Tyr Lys Asp Ser Glu Thr Arg Leu Va #l Glu Val Leu Glu Gly                 85  #                 90  #                 95Val Cys Ser Lys Ser Asp Phe Glu Cys His Ar #g Leu Leu Glu Leu Ser            100       #           105       #           110Glu Glu Leu Val Glu Ser Trp Trp Phe His Ly #s Gln Gln Glu Ala Pro        115           #       120           #       125Asp Leu Phe Gln Trp Leu Cys Ser Asp Ser Le #u Lys Leu Cys Cys Pro    130               #   135               #   140Ala Gly Thr Phe Gly Pro Ser Cys Leu Pro Cy #s Pro Gly Gly Thr Glu145                 1 #50                 1 #55                 1 #60Arg Pro Cys Gly Gly Tyr Gly Gln Cys Glu Gl #y Glu Gly Thr Arg Gly                165   #               170   #               175Gly Ser Gly His Cys Asp Cys Gln Ala Gly Ty #r Gly Gly Glu Ala Cys            180       #           185       #           190Gly Gln Cys Gly Leu Gly Tyr Phe Glu Ala Gl #u Arg Asn Ala Ser His        195           #       200           #       205Leu Val Cys Ser Ala Cys Phe Gly Pro Cys Al #a Arg Cys Ser Gly Pro    210               #   215               #   220Glu Glu Ser Asn Cys Leu Gln Cys Lys Lys Gl #y Trp Ala Leu His His225                 2 #30                 2 #35                 2 #40Leu Lys Cys Val Asp Ile Asp Glu Cys Gly Th #r Glu Gly Ala Asn Cys                245   #               250   #               255Gly Ala Asp Gln Phe Cys Val Asn Thr Glu Gl #y Ser Tyr Glu Cys Arg            260       #           265       #           270Asp Cys Ala Lys Ala Cys Leu Gly Cys Met Gl #y Ala Gly Pro Gly Arg        275           #       280           #       285Cys Lys Lys Cys Ser Pro Gly Tyr Gln Gln Va #l Gly Ser Lys Cys Leu    290               #   295               #   300Asp Val Asp Glu Cys Glu Thr Glu Val Cys Pr #o Gly Glu Asn Lys Gln305                 3 #10                 3 #15                 3 #20Cys Glu Asn Thr Glu Gly Gly Tyr Arg Cys Il #e Cys Ala Glu Gly Tyr                325   #               330   #               335Lys Gln Met Glu Gly Ile Cys Val Lys Glu Gl #n Ile Pro Glu Ser Ala            340       #           345       #           350Gly Phe Phe Ser Glu Met Thr Glu Asp Glu Le #u Val Val Leu Gln Gln        355           #       360           #       365Met Phe Phe Gly Ile Ile Ile Cys Ala Leu Al #a Thr Leu Ala Ala Lys    370               #   375               #   380Gly Asp Leu Val Phe Thr Ala Ile Phe Ile Gl #y Ala Val Ala Ala Met385                 3 #90                 3 #95                 4 #00Thr Gly Tyr Trp Leu Ser Glu Arg Ser Asp Ar #g Val Leu Glu Gly Phe                405   #               410   #               415Ile Lys Gly Arg             420 <210> SEQ ID NO 110 <211> LENGTH: 50<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 110cctggctatc agcaggtggg ctccaagtgt ctcgatgtgg atgagtgtga  #              50 <210> SEQ ID NO 111 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 111attctgcgtg aacactgagg gc            #                  #                 22 <210> SEQ ID NO 112 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 112atctgcttgt agccctcggc ac            #                  #                 22 <210> SEQ ID NO 113 <211> LENGTH: 1616<212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (1461)<223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 113tgagaccctc ctgcagcctt ctcaagggac agccccactc tgcctcttgc tc#ctccaggg     60cagcaccatg cagcccctgt ggctctgctg ggcactctgg gtgttgcccc tg#gccagccc    120cggggccgcc ctgaccgggg agcagctcct gggcagcctg ctgcggcagc tg#cagctcaa    180agaggtgccc accctggaca gggccgacat ggaggagctg gtcatcccca cc#cacgtgag    240ggcccagtac gtggccctgc tgcagcgcag ccacggggac cgctcccgcg ga#aagaggtt    300cagccagagc ttccgagagg tggccggcag gttcctggcg ttggaggcca gc#acacacct    360gctggtgttc ggcatggagc agcggctgcc gcccaacagc gagctggtgc ag#gccgtgct    420gcggctcttc caggagccgg tccccaaggc cgcgctgcac aggcacgggc gg#ctgtcccc    480gcgcagcgcc cgggcccggg tgaccgtcga gtggctgcgc gtccgcgacg ac#ggctccaa    540ccgcacctcc ctcatcgact ccaggctggt gtccgtccac gagagcggct gg#aaggcctt    600cgacgtgacc gaggccgtga acttctggca gcagctgagc cggccccggc ag#ccgctgct    660gctacaggtg tcggtgcaga gggagcatct gggcccgctg gcgtccggcg cc#cacaagct    720ggtccgcttt gcctcgcagg gggcgccagc cgggcttggg gagccccagc tg#gagctgca    780caccctggac cttggggact atggagctca gggcgactgt gaccctgaag ca#ccaatgac    840cgagggcacc cgctgctgcc gccaggagat gtacattgac ctgcagggga tg#aagtgggc    900cgagaactgg gtgctggagc ccccgggctt cctggcttat gagtgtgtgg gc#acctgccg    960gcagcccccg gaggccctgg ccttcaagtg gccgtttctg gggcctcgac ag#tgcatcgc   1020ctcggagact gactcgctgc ccatgatcgt cagcatcaag gagggaggca gg#accaggcc   1080ccaggtggtc agcctgccca acatgagggt gcagaagtgc agctgtgcct cg#gatggtgc   1140gctcgtgcca aggaggctcc agccataggc gcctagtgta gccatcgagg ga#cttgactt   1200gtgtgtgttt ctgaagtgtt cgagggtacc aggagagctg gcgatgactg aa#ctgctgat   1260ggacaaatgc tctgtgctct ctagtgagcc ctgaatttgc ttcctctgac aa#gttacctc   1320acctaatttt tgcttctcag gaatgagaat ctttggccac tggagagccc tt#gctcagtt   1380ttctctattc ttattattca ctgcactata ttctaagcac ttacatgtgg ag#atactgta   1440acctgagggc agaaagccca ntgtgtcatt gtttacttgt cctgtcactg ga#tctgggct   1500aaagtcctcc accaccactc tggacctaag acctggggtt aagtgtgggt tg#tgcatccc   1560caatccagat aataaagact ttgtaaaaca tgaataaaac acattttatt ct#aaaa       1616 <210> SEQ ID NO 114 <211> LENGTH: 366 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 114Met Gln Pro Leu Trp Leu Cys Trp Ala Leu Tr #p Val Leu Pro Leu Ala  1               5  #                 10  #                 15Ser Pro Gly Ala Ala Leu Thr Gly Glu Gln Le #u Leu Gly Ser Leu Leu             20      #             25      #             30Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Le #u Asp Arg Ala Asp Met         35          #         40          #         45Glu Glu Leu Val Ile Pro Thr His Val Arg Al #a Gln Tyr Val Ala Leu     50              #     55              #     60Leu Gln Arg Ser His Gly Asp Arg Ser Arg Gl #y Lys Arg Phe Ser Gln 65                  # 70                  # 75                  # 80Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Al #a Leu Glu Ala Ser Thr                 85  #                 90  #                 95His Leu Leu Val Phe Gly Met Glu Gln Arg Le #u Pro Pro Asn Ser Glu            100       #           105       #           110Leu Val Gln Ala Val Leu Arg Leu Phe Gln Gl #u Pro Val Pro Lys Ala        115           #       120           #       125Ala Leu His Arg His Gly Arg Leu Ser Pro Ar #g Ser Ala Arg Ala Arg    130               #   135               #   140Val Thr Val Glu Trp Leu Arg Val Arg Asp As #p Gly Ser Asn Arg Thr145                 1 #50                 1 #55                 1 #60Ser Leu Ile Asp Ser Arg Leu Val Ser Val Hi #s Glu Ser Gly Trp Lys                165   #               170   #               175Ala Phe Asp Val Thr Glu Ala Val Asn Phe Tr #p Gln Gln Leu Ser Arg            180       #           185       #           190Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Va #l Gln Arg Glu His Leu        195           #       200           #       205Gly Pro Leu Ala Ser Gly Ala His Lys Leu Va #l Arg Phe Ala Ser Gln    210               #   215               #   220Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Le #u Glu Leu His Thr Leu225                 2 #30                 2 #35                 2 #40Asp Leu Gly Asp Tyr Gly Ala Gln Gly Asp Cy #s Asp Pro Glu Ala Pro                245   #               250   #               255Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Gl #u Met Tyr Ile Asp Leu            260       #           265       #           270Gln Gly Met Lys Trp Ala Glu Asn Trp Val Le #u Glu Pro Pro Gly Phe        275           #       280           #       285Leu Ala Tyr Glu Cys Val Gly Thr Cys Arg Gl #n Pro Pro Glu Ala Leu    290               #   295               #   300Ala Phe Lys Trp Pro Phe Leu Gly Pro Arg Gl #n Cys Ile Ala Ser Glu305                 3 #10                 3 #15                 3 #20Thr Asp Ser Leu Pro Met Ile Val Ser Ile Ly #s Glu Gly Gly Arg Thr                325   #               330   #               335Arg Pro Gln Val Val Ser Leu Pro Asn Met Ar #g Val Gln Lys Cys Ser            340       #           345       #           350Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Ar #g Leu Gln Pro        355           #       360           #       365<210> SEQ ID NO 115 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 115aggactgcca taacttgcct g            #                  #                   #21 <210> SEQ ID NO 116 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 116ataggagttg aagcagcgct gc            #                  #                 22 <210> SEQ ID NO 117 <211> LENGTH: 45<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 117tgtgtggaca tagacgagtg ccgctaccgc tactgccagc accgc    #                  #45 <210> SEQ ID NO 118 <211> LENGTH: 1857 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 118gtctgttccc aggagtcctt cggcggctgt tgtgtcagtg gcctgatcgc ga#tggggaca     60aaggcgcaag tcgagaggaa actgttgtgc ctcttcatat tggcgatcct gt#tgtgctcc    120ctggcattgg gcagtgttac agtgcactct tctgaacctg aagtcagaat tc#ctgagaat    180aatcctgtga agttgtcctg tgcctactcg ggcttttctt ctccccgtgt gg#agtggaag    240tttgaccaag gagacaccac cagactcgtt tgctataata acaagatcac ag#cttcctat    300gaggaccggg tgaccttctt gccaactggt atcaccttca agtccgtgac ac#gggaagac    360actgggacat acacttgtat ggtctctgag gaaggcggca acagctatgg gg#aggtcaag    420gtcaagctca tcgtgcttgt gcctccatcc aagcctacag ttaacatccc ct#cctctgcc    480accattggga accgggcagt gctgacatgc tcagaacaag atggttcccc ac#cttctgaa    540tacacctggt tcaaagatgg gatagtgatg cctacgaatc ccaaaagcac cc#gtgccttc    600agcaactctt cctatgtcct gaatcccaca acaggagagc tggtctttga tc#ccctgtca    660gcctctgata ctggagaata cagctgtgag gcacggaatg ggtatgggac ac#ccatgact    720tcaaatgctg tgcgcatgga agctgtggag cggaatgtgg gggtcatcgt gg#cagccgtc    780cttgtaaccc tgattctcct gggaatcttg gtttttggca tctggtttgc ct#atagccga    840ggccactttg acagaacaaa gaaagggact tcgagtaaga aggtgattta ca#gccagcct    900agtgcccgaa gtgaaggaga attcaaacag acctcgtcat tcctggtgtg ag#cctggtcg    960gctcaccgcc tatcatctgc atttgcctta ctcaggtgct accggactct gg#cccctgat   1020gtctgtagtt tcacaggatg ccttatttgt cttctacacc ccacagggcc cc#ctacttct   1080tcggatgtgt ttttaataat gtcagctatg tgccccatcc tccttcatgc cc#tccctccc   1140tttcctacca ctgctgagtg gcctggaact tgtttaaagt gtttattccc ca#tttctttg   1200agggatcagg aaggaatcct gggtatgcca ttgacttccc ttctaagtag ac#agcaaaaa   1260tggcgggggt cgcaggaatc tgcactcaac tgcccacctg gctggcaggg at#ctttgaat   1320aggtatcttg agcttggttc tgggctcttt ccttgtgtac tgacgaccag gg#ccagctgt   1380tctagagcgg gaattagagg ctagagcggc tgaaatggtt gtttggtgat ga#cactgggg   1440tccttccatc tctggggccc actctcttct gtcttcccat gggaagtgcc ac#tgggatcc   1500ctctgccctg tcctcctgaa tacaagctga ctgacattga ctgtgtctgt gg#aaaatggg   1560agctcttgtt gtggagagca tagtaaattt tcagagaact tgaagccaaa ag#gatttaaa   1620accgctgctc taaagaaaag aaaactggag gctgggcgca gtggctcacg cc#tgtaatcc   1680cagaggctga ggcaggcgga tcacctgagg tcgggagttc gggatcagcc tg#accaacat   1740ggagaaaccc tactggaaat acaaagttag ccaggcatgg tggtgcatgc ct#gtagtccc   1800agctgctcag gagcctggca acaagagcaa aactccagct caaaaaaaaa aa#aaaaa      1857 <210> SEQ ID NO 119 <211> LENGTH: 299 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 119Met Gly Thr Lys Ala Gln Val Glu Arg Lys Le #u Leu Cys Leu Phe Ile  1               5  #                 10  #                 15Leu Ala Ile Leu Leu Cys Ser Leu Ala Leu Gl #y Ser Val Thr Val His             20      #             25      #             30Ser Ser Glu Pro Glu Val Arg Ile Pro Glu As #n Asn Pro Val Lys Leu         35          #         40          #         45Ser Cys Ala Tyr Ser Gly Phe Ser Ser Pro Ar #g Val Glu Trp Lys Phe     50              #     55              #     60Asp Gln Gly Asp Thr Thr Arg Leu Val Cys Ty #r Asn Asn Lys Ile Thr 65                  # 70                  # 75                  # 80Ala Ser Tyr Glu Asp Arg Val Thr Phe Leu Pr #o Thr Gly Ile Thr Phe                 85  #                 90  #                 95Lys Ser Val Thr Arg Glu Asp Thr Gly Thr Ty #r Thr Cys Met Val Ser            100       #           105       #           110Glu Glu Gly Gly Asn Ser Tyr Gly Glu Val Ly #s Val Lys Leu Ile Val        115           #       120           #       125Leu Val Pro Pro Ser Lys Pro Thr Val Asn Il #e Pro Ser Ser Ala Thr    130               #   135               #   140Ile Gly Asn Arg Ala Val Leu Thr Cys Ser Gl #u Gln Asp Gly Ser Pro145                 1 #50                 1 #55                 1 #60Pro Ser Glu Tyr Thr Trp Phe Lys Asp Gly Il #e Val Met Pro Thr Asn                165   #               170   #               175Pro Lys Ser Thr Arg Ala Phe Ser Asn Ser Se #r Tyr Val Leu Asn Pro            180       #           185       #           190Thr Thr Gly Glu Leu Val Phe Asp Pro Leu Se #r Ala Ser Asp Thr Gly        195           #       200           #       205Glu Tyr Ser Cys Glu Ala Arg Asn Gly Tyr Gl #y Thr Pro Met Thr Ser    210               #   215               #   220Asn Ala Val Arg Met Glu Ala Val Glu Arg As #n Val Gly Val Ile Val225                 2 #30                 2 #35                 2 #40Ala Ala Val Leu Val Thr Leu Ile Leu Leu Gl #y Ile Leu Val Phe Gly                245   #               250   #               255Ile Trp Phe Ala Tyr Ser Arg Gly His Phe As #p Arg Thr Lys Lys Gly            260       #           265       #           270Thr Ser Ser Lys Lys Val Ile Tyr Ser Gln Pr #o Ser Ala Arg Ser Glu        275           #       280           #       285Gly Glu Phe Lys Gln Thr Ser Ser Phe Leu Va #l     290              #   295 <210> SEQ ID NO 120 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 120tcgcggagct gtgttctgtt tccc           #                  #                24 <210> SEQ ID NO 121 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 121tgatcgcgat ggggacaaag gcgcaagctc gagaggaaac tgttgtgcct  #              50 <210> SEQ ID NO 122 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 122acacctggtt caaagatggg             #                  #                   # 20 <210> SEQ ID NO 123 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 123taggaagagt tgctgaaggc acgg           #                  #                24 <210> SEQ ID NO 124 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 124ttgccttact caggtgctac             #                  #                   # 20 <210> SEQ ID NO 125 <211> LENGTH: 20<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 125actcagcagt ggtaggaaag             #                  #                   # 20 <210> SEQ ID NO 126 <211> LENGTH: 1210<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 126cagcgcgtgg ccggcgccgc tgtggggaca gcatgagcgg cggttggatg gc#gcaggttg     60gagcgtggcg aacaggggct ctgggcctgg cgctgctgct gctgctcggc ct#cggactag    120gcctggaggc cgccgcgagc ccgctttcca ccccgacctc tgcccaggcc gc#aggcccca    180gctcaggctc gtgcccaccc accaagttcc agtgccgcac cagtggctta tg#cgtgcccc    240tcacctggcg ctgcgacagg gacttggact gcagcgatgg cagcgatgag ga#ggagtgca    300ggattgagcc atgtacccag aaagggcaat gcccaccgcc ccctggcctc cc#ctgcccct    360gcaccggcgt cagtgactgc tctgggggaa ctgacaagaa actgcgcaac tg#cagccgcc    420tggcctgcct agcaggcgag ctccgttgca cgctgagcga tgactgcatt cc#actcacgt    480ggcgctgcga cggccaccca gactgtcccg actccagcga cgagctcggc tg#tggaacca    540atgagatcct cccggaaggg gatgccacaa ccatggggcc ccctgtgacc ct#ggagagtg    600tcacctctct caggaatgcc acaaccatgg ggccccctgt gaccctggag ag#tgtcccct    660ctgtcgggaa tgccacatcc tcctctgccg gagaccagtc tggaagccca ac#tgcctatg    720gggttattgc agctgctgcg gtgctcagtg caagcctggt caccgccacc ct#cctccttt    780tgtcctggct ccgagcccag gagcgcctcc gcccactggg gttactggtg gc#catgaagg    840agtccctgct gctgtcagaa cagaagacct cgctgccctg aggacaagca ct#tgccacca    900ccgtcactca gccctgggcg tagccggaca ggaggagagc agtgatgcgg at#gggtaccc    960gggcacacca gccctcagag acctgagttc ttctggccac gtggaacctc ga#acccgagc   1020tcctgcagaa gtggccctgg agattgaggg tccctggaca ctccctatgg ag#atccgggg   1080agctaggatg gggaacctgc cacagccaga actgaggggc tggccccagg ca#gctcccag   1140ggggtagaac ggccctgtgc ttaagacact ccctgctgcc ccgtctgagg gt#ggcgatta   1200 aagttgcttc                 #                  #                   #      1210 <210> SEQ ID NO 127 <211> LENGTH: 282<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 127Met Ser Gly Gly Trp Met Ala Gln Val Gly Al #a Trp Arg Thr Gly Ala  1               5  #                 10  #                 15Leu Gly Leu Ala Leu Leu Leu Leu Leu Gly Le #u Gly Leu Gly Leu Glu             20      #             25      #             30Ala Ala Ala Ser Pro Leu Ser Thr Pro Thr Se #r Ala Gln Ala Ala Gly         35          #         40          #         45Pro Ser Ser Gly Ser Cys Pro Pro Thr Lys Ph #e Gln Cys Arg Thr Ser     50              #     55              #     60Gly Leu Cys Val Pro Leu Thr Trp Arg Cys As #p Arg Asp Leu Asp Cys 65                  # 70                  # 75                  # 80Ser Asp Gly Ser Asp Glu Glu Glu Cys Arg Il #e Glu Pro Cys Thr Gln                 85  #                 90  #                 95Lys Gly Gln Cys Pro Pro Pro Pro Gly Leu Pr #o Cys Pro Cys Thr Gly            100       #           105       #           110Val Ser Asp Cys Ser Gly Gly Thr Asp Lys Ly #s Leu Arg Asn Cys Ser        115           #       120           #       125Arg Leu Ala Cys Leu Ala Gly Glu Leu Arg Cy #s Thr Leu Ser Asp Asp    130               #   135               #   140Cys Ile Pro Leu Thr Trp Arg Cys Asp Gly Hi #s Pro Asp Cys Pro Asp145                 1 #50                 1 #55                 1 #60Ser Ser Asp Glu Leu Gly Cys Gly Thr Asn Gl #u Ile Leu Pro Glu Gly                165   #               170   #               175Asp Ala Thr Thr Met Gly Pro Pro Val Thr Le #u Glu Ser Val Thr Ser            180       #           185       #           190Leu Arg Asn Ala Thr Thr Met Gly Pro Pro Va #l Thr Leu Glu Ser Val        195           #       200           #       205Pro Ser Val Gly Asn Ala Thr Ser Ser Ser Al #a Gly Asp Gln Ser Gly    210               #   215               #   220Ser Pro Thr Ala Tyr Gly Val Ile Ala Ala Al #a Ala Val Leu Ser Ala225                 2 #30                 2 #35                 2 #40Ser Leu Val Thr Ala Thr Leu Leu Leu Leu Se #r Trp Leu Arg Ala Gln                245   #               250   #               255Glu Arg Leu Arg Pro Leu Gly Leu Leu Val Al #a Met Lys Glu Ser Leu            260       #           265       #           270Leu Leu Ser Glu Gln Lys Thr Ser Leu Pro         275          #       280 <210> SEQ ID NO 128 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 128aagttccagt gccgcaccag tggc           #                  #                24 <210> SEQ ID NO 129 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 129ttggttccac agccgagctc gtcg           #                  #                24 <210> SEQ ID NO 130 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 130gaggaggagt gcaggattga gccatgtacc cagaaagggc aatgcccacc  #              50 <210> SEQ ID NO 131 <211> LENGTH: 1843 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (1837)<223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 131cccacgcgtc cggtctcgct cgctcgcgca gcggcggcag cagaggtcgc gc#acagatgc     60gggttagact ggcgggggga ggaggcggag gagggaagga agctgcatgc at#gagaccca    120cagactcttg caagctggat gccctctgtg gatgaaagat gtatcatgga at#gaacccga    180gcaatggaga tggatttcta gagcagcagc agcagcagca gcaacctcag tc#cccccaga    240gactcttggc cgtgatcctg tggtttcagc tggcgctgtg cttcggccct gc#acagctca    300cgggcgggtt cgatgacctt caagtgtgtg ctgaccccgg cattcccgag aa#tggcttca    360ggacccccag cggaggggtt ttctttgaag gctctgtagc ccgatttcac tg#ccaagacg    420gattcaagct gaagggcgct acaaagagac tgtgtttgaa gcattttaat gg#aaccctag    480gctggatccc aagtgataat tccatctgtg tgcaagaaga ttgccgtatc cc#tcaaatcg    540aagatgctga gattcataac aagacatata gacatggaga gaagctaatc at#cacttgtc    600atgaaggatt caagatccgg taccccgacc tacacaatat ggtttcatta tg#tcgcgatg    660atggaacgtg gaataatctg cccatctgtc aaggctgcct gagacctcta gc#ctcttcta    720atggctatgt aaacatctct gagctccaga cctccttccc ggtggggact gt#gatctcct    780atcgctgctt tcccggattt aaacttgatg ggtctgcgta tcttgagtgc tt#acaaaacc    840ttatctggtc gtccagccca ccccggtgcc ttgctctgga agcccaagtc tg#tccactac    900ctccaatggt gagtcacgga gatttcgtct gccacccgcg gccttgtgag cg#ctacaacc    960acggaactgt ggtggagttt tactgcgatc ctggctacag cctcaccagc ga#ctacaagt   1020acatcacctg ccagtatgga gagtggtttc cttcttatca agtctactgc at#caaatcag   1080agcaaacgtg gcccagcacc catgagaccc tcctgaccac gtggaagatt gt#ggcgttca   1140cggcaaccag tgtgctgctg gtgctgctgc tcgtcatcct ggccaggatg tt#ccagacca   1200agttcaaggc ccactttccc cccagggggc ctccccggag ttccagcagt ga#ccctgact   1260ttgtggtggt agacggcgtg cccgtcatgc tcccgtccta tgacgaagct gt#gagtggcg   1320gcttgagtgc cttaggcccc gggtacatgg cctctgtggg ccagggctgc cc#cttacccg   1380tggacgacca gagcccccca gcataccccg gctcagggga cacggacaca gg#cccagggg   1440agtcagaaac ctgtgacagc gtctcaggct cttctgagct gctccaaagt ct#gtattcac   1500ctcccaggtg ccaagagagc acccaccctg cttcggacaa ccctgacata at#tgccagca   1560cggcagagga ggtggcatcc accagcccag gcatccatca tgcccactgg gt#gttgttcc   1620taagaaactg attgattaaa aaatttccca aagtgtcctg aagtgtctct tc#aaatacat   1680gttgatctgt ggagttgatt cctttccttc tcttggtttt agacaaatgt aa#acaaagct   1740ctgatcctta aaattgctat gctgatagag tggtgagggc tggaagcttg at#caagtcct   1800 gtttcttctt gacacagact gattaaaaat taaaagnaaa aaa    #                 184 #3 <210> SEQ ID NO 132 <211> LENGTH: 490<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 132Met Tyr His Gly Met Asn Pro Ser Asn Gly As #p Gly Phe Leu Glu Gln  1               5  #                 10  #                 15Gln Gln Gln Gln Gln Gln Pro Gln Ser Pro Gl #n Arg Leu Leu Ala Val             20      #             25      #             30Ile Leu Trp Phe Gln Leu Ala Leu Cys Phe Gl #y Pro Ala Gln Leu Thr         35          #         40          #         45Gly Gly Phe Asp Asp Leu Gln Val Cys Ala As #p Pro Gly Ile Pro Glu     50              #     55              #     60Asn Gly Phe Arg Thr Pro Ser Gly Gly Val Ph #e Phe Glu Gly Ser Val 65                  # 70                  # 75                  # 80Ala Arg Phe His Cys Gln Asp Gly Phe Lys Le #u Lys Gly Ala Thr Lys                 85  #                 90  #                 95Arg Leu Cys Leu Lys His Phe Asn Gly Thr Le #u Gly Trp Ile Pro Ser            100       #           105       #           110Asp Asn Ser Ile Cys Val Gln Glu Asp Cys Ar #g Ile Pro Gln Ile Glu        115           #       120           #       125Asp Ala Glu Ile His Asn Lys Thr Tyr Arg Hi #s Gly Glu Lys Leu Ile    130               #   135               #   140Ile Thr Cys His Glu Gly Phe Lys Ile Arg Ty #r Pro Asp Leu His Asn145                 1 #50                 1 #55                 1 #60Met Val Ser Leu Cys Arg Asp Asp Gly Thr Tr #p Asn Asn Leu Pro Ile                165   #               170   #               175Cys Gln Gly Cys Leu Arg Pro Leu Ala Ser Se #r Asn Gly Tyr Val Asn            180       #           185       #           190Ile Ser Glu Leu Gln Thr Ser Phe Pro Val Gl #y Thr Val Ile Ser Tyr        195           #       200           #       205Arg Cys Phe Pro Gly Phe Lys Leu Asp Gly Se #r Ala Tyr Leu Glu Cys    210               #   215               #   220Leu Gln Asn Leu Ile Trp Ser Ser Ser Pro Pr #o Arg Cys Leu Ala Leu225                 2 #30                 2 #35                 2 #40Glu Ala Gln Val Cys Pro Leu Pro Pro Met Va #l Ser His Gly Asp Phe                245   #               250   #               255Val Cys His Pro Arg Pro Cys Glu Arg Tyr As #n His Gly Thr Val Val            260       #           265       #           270Glu Phe Tyr Cys Asp Pro Gly Tyr Ser Leu Th #r Ser Asp Tyr Lys Tyr        275           #       280           #       285Ile Thr Cys Gln Tyr Gly Glu Trp Phe Pro Se #r Tyr Gln Val Tyr Cys    290               #   295               #   300Ile Lys Ser Glu Gln Thr Trp Pro Ser Thr Hi #s Glu Thr Leu Leu Thr305                 3 #10                 3 #15                 3 #20Thr Trp Lys Ile Val Ala Phe Thr Ala Thr Se #r Val Leu Leu Val Leu                325   #               330   #               335Leu Leu Val Ile Leu Ala Arg Met Phe Gln Th #r Lys Phe Lys Ala His            340       #           345       #           350Phe Pro Pro Arg Gly Pro Pro Arg Ser Ser Se #r Ser Asp Pro Asp Phe        355           #       360           #       365Val Val Val Asp Gly Val Pro Val Met Leu Pr #o Ser Tyr Asp Glu Ala    370               #   375               #   380Val Ser Gly Gly Leu Ser Ala Leu Gly Pro Gl #y Tyr Met Ala Ser Val385                 3 #90                 3 #95                 4 #00Gly Gln Gly Cys Pro Leu Pro Val Asp Asp Gl #n Ser Pro Pro Ala Tyr                405   #               410   #               415Pro Gly Ser Gly Asp Thr Asp Thr Gly Pro Gl #y Glu Ser Glu Thr Cys            420       #           425       #           430Asp Ser Val Ser Gly Ser Ser Glu Leu Leu Gl #n Ser Leu Tyr Ser Pro        435           #       440           #       445Pro Arg Cys Gln Glu Ser Thr His Pro Ala Se #r Asp Asn Pro Asp Ile    450               #   455               #   460Ile Ala Ser Thr Ala Glu Glu Val Ala Ser Th #r Ser Pro Gly Ile His465                 4 #70                 4 #75                 4 #80His Ala His Trp Val Leu Phe Leu Arg Asn                 485  #               490 <210> SEQ ID NO 133 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 133atctcctatc gctgctttcc cgg            #                  #                23 <210> SEQ ID NO 134 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 134agccaggatc gcagtaaaac tcc            #                  #                23 <210> SEQ ID NO 135 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 135atttaaactt gatgggtctg cgtatcttga gtgcttacaa aaccttatct  #              50 <210> SEQ ID NO 136 <211> LENGTH: 1815 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 136cccacgcgtc cgctccgcgc cctccccccc gcctcccgtg cggtccgtcg gt#ggcctaga     60gatgctgctg ccgcggttgc agttgtcgcg cacgcctctg cccgccagcc cg#ctccaccg    120ccgtagcgcc cgagtgtcgg ggggcgcacc cgagtcgggc catgaggccg gg#aaccgcgc    180tacaggccgt gctgctggcc gtgctgctgg tggggctgcg ggccgcgacg gg#tcgcctgc    240tgagtgcctc ggatttggac ctcagaggag ggcagccagt ctgccgggga gg#gacacaga    300ggccttgtta taaagtcatt tacttccatg atacttctcg aagactgaac tt#tgaggaag    360ccaaagaagc ctgcaggagg gatggaggcc agctagtcag catcgagtct ga#agatgaac    420agaaactgat agaaaagttc attgaaaacc tcttgccatc tgatggtgac tt#ctggattg    480ggctcaggag gcgtgaggag aaacaaagca atagcacagc ctgccaggac ct#ttatgctt    540ggactgatgg cagcatatca caatttagga actggtatgt ggatgagccg tc#ctgcggca    600gcgaggtctg cgtggtcatg taccatcagc catcggcacc cgctggcatc gg#aggcccct    660acatgttcca gtggaatgat gaccggtgca acatgaagaa caatttcatt tg#caaatatt    720ctgatgagaa accagcagtt ccttctagag aagctgaagg tgaggaaaca ga#gctgacaa    780cacctgtact tccagaagaa acacaggaag aagatgccaa aaaaacattt aa#agaaagta    840gagaagctgc cttgaatctg gcctacatcc taatccccag cattcccctt ct#cctcctcc    900ttgtggtcac cacagttgta tgttgggttt ggatctgtag aaaaagaaaa cg#ggagcagc    960cagaccctag cacaaagaag caacacacca tctggccctc tcctcaccag gg#aaacagcc   1020cggacctaga ggtctacaat gtcataagaa aacaaagcga agctgactta gc#tgagaccc   1080ggccagacct gaagaatatt tcattccgag tgtgttcggg agaagccact cc#cgatgaca   1140tgtcttgtga ctatgacaac atggctgtga acccatcaga aagtgggttt gt#gactctgg   1200tgagcgtgga gagtggattt gtgaccaatg acatttatga gttctcccca ga#ccaaatgg   1260ggaggagtaa ggagtctgga tgggtggaaa atgaaatata tggttattag ga#catataaa   1320aaactgaaac tgacaacaat ggaaaagaaa tgataagcaa aatcctctta tt#ttctataa   1380ggaaaataca cagaaggtct atgaacaagc ttagatcagg tcctgtggat ga#gcatgtgg   1440tccccacgac ctcctgttgg acccccacgt tttggctgta tcctttatcc ca#gccagtca   1500tccagctcga ccttatgaga aggtaccttg cccaggtctg gcacatagta ga#gtctcaat   1560aaatgtcact tggttggttg tatctaactt ttaagggaca gagctttacc tg#gcagtgat   1620aaagatgggc tgtggagctt ggaaaaccac ctctgttttc cttgctctat ac#agcagcac   1680atattatcat acagacagaa aatccagaat cttttcaaag cccacatatg gt#agcacagg   1740ttggcctgtg catcggcaat tctcatatct gtttttttca aagaataaaa tc#aaataaag   1800 agcaggaaaa aaaaa               #                  #                   #  1815 <210> SEQ ID NO 137 <211> LENGTH: 382<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 137Met Arg Pro Gly Thr Ala Leu Gln Ala Val Le #u Leu Ala Val Leu Leu  1               5  #                 10  #                 15Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Le #u Ser Ala Ser Asp Leu             20      #             25      #             30Asp Leu Arg Gly Gly Gln Pro Val Cys Arg Gl #y Gly Thr Gln Arg Pro         35          #         40          #         45Cys Tyr Lys Val Ile Tyr Phe His Asp Thr Se #r Arg Arg Leu Asn Phe     50              #     55              #     60Glu Glu Ala Lys Glu Ala Cys Arg Arg Asp Gl #y Gly Gln Leu Val Ser 65                  # 70                  # 75                  # 80Ile Glu Ser Glu Asp Glu Gln Lys Leu Ile Gl #u Lys Phe Ile Glu Asn                 85  #                 90  #                 95Leu Leu Pro Ser Asp Gly Asp Phe Trp Ile Gl #y Leu Arg Arg Arg Glu            100       #           105       #           110Glu Lys Gln Ser Asn Ser Thr Ala Cys Gln As #p Leu Tyr Ala Trp Thr        115           #       120           #       125Asp Gly Ser Ile Ser Gln Phe Arg Asn Trp Ty #r Val Asp Glu Pro Ser    130               #   135               #   140Cys Gly Ser Glu Val Cys Val Val Met Tyr Hi #s Gln Pro Ser Ala Pro145                 1 #50                 1 #55                 1 #60Ala Gly Ile Gly Gly Pro Tyr Met Phe Gln Tr #p Asn Asp Asp Arg Cys                165   #               170   #               175Asn Met Lys Asn Asn Phe Ile Cys Lys Tyr Se #r Asp Glu Lys Pro Ala            180       #           185       #           190Val Pro Ser Arg Glu Ala Glu Gly Glu Glu Th #r Glu Leu Thr Thr Pro        195           #       200           #       205Val Leu Pro Glu Glu Thr Gln Glu Glu Asp Al #a Lys Lys Thr Phe Lys    210               #   215               #   220Glu Ser Arg Glu Ala Ala Leu Asn Leu Ala Ty #r Ile Leu Ile Pro Ser225                 2 #30                 2 #35                 2 #40Ile Pro Leu Leu Leu Leu Leu Val Val Thr Th #r Val Val Cys Trp Val                245   #               250   #               255Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pr #o Asp Pro Ser Thr Lys            260       #           265       #           270Lys Gln His Thr Ile Trp Pro Ser Pro His Gl #n Gly Asn Ser Pro Asp        275           #       280           #       285Leu Glu Val Tyr Asn Val Ile Arg Lys Gln Se #r Glu Ala Asp Leu Ala    290               #   295               #   300Glu Thr Arg Pro Asp Leu Lys Asn Ile Ser Ph #e Arg Val Cys Ser Gly305                 3 #10                 3 #15                 3 #20Glu Ala Thr Pro Asp Asp Met Ser Cys Asp Ty #r Asp Asn Met Ala Val                325   #               330   #               335Asn Pro Ser Glu Ser Gly Phe Val Thr Leu Va #l Ser Val Glu Ser Gly            340       #           345       #           350Phe Val Thr Asn Asp Ile Tyr Glu Phe Ser Pr #o Asp Gln Met Gly Arg        355           #       360           #       365Ser Lys Glu Ser Gly Trp Val Glu Asn Glu Il #e Tyr Gly Tyr    370               #   375               #   380 <210> SEQ ID NO 138<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 138gttcattgaa aacctcttgc catctgatgg tgacttctgg attgggctca  #              50 <210> SEQ ID NO 139 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 139aagccaaaga agcctgcagg aggg           #                  #                24 <210> SEQ ID NO 140 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 140cagtccaagc ataaaggtcc tggc           #                  #                24 <210> SEQ ID NO 141 <211> LENGTH: 1514<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 141ggggtctccc tcagggccgg gaggcacagc ggtccctgct tgctgaaggg ct#ggatgtac     60gcatccgcag gttcccgcgg acttgggggc gcccgctgag ccccggcgcc cg#cagaagac    120ttgtgtttgc ctcctgcagc ctcaacccgg agggcagcga gggcctacca cc#atgatcac    180tggtgtgttc agcatgcgct tgtggacccc agtgggcgtc ctgacctcgc tg#gcgtactg    240cctgcaccag cggcgggtgg ccctggccga gctgcaggag gccgatggcc ag#tgtccggt    300cgaccgcagc ctgctgaagt tgaaaatggt gcaggtcgtg tttcgacacg gg#gctcggag    360tcctctcaag ccgctcccgc tggaggagca ggtagagtgg aacccccagc ta#ttagaggt    420cccaccccaa actcagtttg attacacagt caccaatcta gctggtggtc cg#aaaccata    480ttctccttac gactctcaat accatgagac caccctgaag gggggcatgt tt#gctgggca    540gctgaccaag gtgggcatgc agcaaatgtt tgccttggga gagagactga gg#aagaacta    600tgtggaagac attccctttc tttcaccaac cttcaaccca caggaggtct tt#attcgttc    660cactaacatt tttcggaatc tggagtccac ccgttgtttg ctggctgggc tt#ttccagtg    720tcagaaagaa ggacccatca tcatccacac tgatgaagca gattcagaag tc#ttgtatcc    780caactaccaa agctgctgga gcctgaggca gagaaccaga ggccggaggc ag#actgcctc    840tttacagcca ggaatctcag aggatttgaa aaaggtgaag gacaggatgg gc#attgacag    900tagtgataaa gtggacttct tcatcctcct ggacaacgtg gctgccgagc ag#gcacacaa    960cctcccaagc tgccccatgc tgaagagatt tgcacggatg atcgaacaga ga#gctgtgga   1020cacatccttg tacatactgc ccaaggaaga cagggaaagt cttcagatgg ca#gtaggccc   1080attcctccac atcctagaga gcaacctgct gaaagccatg gactctgcca ct#gcccccga   1140caagatcaga aagctgtatc tctatgcggc tcatgatgtg accttcatac cg#ctcttaat   1200gaccctgggg atttttgacc acaaatggcc accgtttgct gttgacctga cc#atggaact   1260ttaccagcac ctggaatcta aggagtggtt tgtgcagctc tattaccacg gg#aaggagca   1320ggtgccgaga ggttgccctg atgggctctg cccgctggac atgttcttga at#gccatgtc   1380agtttatacc ttaagcccag aaaaatacca tgcactctgc tctcaaactc ag#gtgatgga   1440agttggaaat gaagagtaac tgatttataa aagcaggatg tgttgatttt aa#aataaagt   1500 gcctttatac aatg               #                  #                   #   1514 <210> SEQ ID NO 142 <211> LENGTH: 428<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 142Met Ile Thr Gly Val Phe Ser Met Arg Leu Tr #p Thr Pro Val Gly Val  1               5  #                 10  #                 15Leu Thr Ser Leu Ala Tyr Cys Leu His Gln Ar #g Arg Val Ala Leu Ala             20      #             25      #             30Glu Leu Gln Glu Ala Asp Gly Gln Cys Pro Va #l Asp Arg Ser Leu Leu         35          #         40          #         45Lys Leu Lys Met Val Gln Val Val Phe Arg Hi #s Gly Ala Arg Ser Pro     50              #     55              #     60Leu Lys Pro Leu Pro Leu Glu Glu Gln Val Gl #u Trp Asn Pro Gln Leu 65                  # 70                  # 75                  # 80Leu Glu Val Pro Pro Gln Thr Gln Phe Asp Ty #r Thr Val Thr Asn Leu                 85  #                 90  #                 95Ala Gly Gly Pro Lys Pro Tyr Ser Pro Tyr As #p Ser Gln Tyr His Glu            100       #           105       #           110Thr Thr Leu Lys Gly Gly Met Phe Ala Gly Gl #n Leu Thr Lys Val Gly        115           #       120           #       125Met Gln Gln Met Phe Ala Leu Gly Glu Arg Le #u Arg Lys Asn Tyr Val    130               #   135               #   140Glu Asp Ile Pro Phe Leu Ser Pro Thr Phe As #n Pro Gln Glu Val Phe145                 1 #50                 1 #55                 1 #60Ile Arg Ser Thr Asn Ile Phe Arg Asn Leu Gl #u Ser Thr Arg Cys Leu                165   #               170   #               175Leu Ala Gly Leu Phe Gln Cys Gln Lys Glu Gl #y Pro Ile Ile Ile His            180       #           185       #           190Thr Asp Glu Ala Asp Ser Glu Val Leu Tyr Pr #o Asn Tyr Gln Ser Cys        195           #       200           #       205Trp Ser Leu Arg Gln Arg Thr Arg Gly Arg Ar #g Gln Thr Ala Ser Leu    210               #   215               #   220Gln Pro Gly Ile Ser Glu Asp Leu Lys Lys Va #l Lys Asp Arg Met Gly225                 2 #30                 2 #35                 2 #40Ile Asp Ser Ser Asp Lys Val Asp Phe Phe Il #e Leu Leu Asp Asn Val                245   #               250   #               255Ala Ala Glu Gln Ala His Asn Leu Pro Ser Cy #s Pro Met Leu Lys Arg            260       #           265       #           270Phe Ala Arg Met Ile Glu Gln Arg Ala Val As #p Thr Ser Leu Tyr Ile        275           #       280           #       285Leu Pro Lys Glu Asp Arg Glu Ser Leu Gln Me #t Ala Val Gly Pro Phe    290               #   295               #   300Leu His Ile Leu Glu Ser Asn Leu Leu Lys Al #a Met Asp Ser Ala Thr305                 3 #10                 3 #15                 3 #20Ala Pro Asp Lys Ile Arg Lys Leu Tyr Leu Ty #r Ala Ala His Asp Val                325   #               330   #               335Thr Phe Ile Pro Leu Leu Met Thr Leu Gly Il #e Phe Asp His Lys Trp            340       #           345       #           350Pro Pro Phe Ala Val Asp Leu Thr Met Glu Le #u Tyr Gln His Leu Glu        355           #       360           #       365Ser Lys Glu Trp Phe Val Gln Leu Tyr Tyr Hi #s Gly Lys Glu Gln Val    370               #   375               #   380Pro Arg Gly Cys Pro Asp Gly Leu Cys Pro Le #u Asp Met Phe Leu Asn385                 3 #90                 3 #95                 4 #00Ala Met Ser Val Tyr Thr Leu Ser Pro Glu Ly #s Tyr His Ala Leu Cys                405   #               410   #               415Ser Gln Thr Gln Val Met Glu Val Gly Asn Gl #u Glu             420      #           425 <210> SEQ ID NO 143 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 143ccaactacca aagctgctgg agcc           #                  #                24 <210> SEQ ID NO 144 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 144gcagctctat taccacggga agga           #                  #                24 <210> SEQ ID NO 145 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 145tccttcccgt ggtaatagag ctgc           #                  #                24 <210> SEQ ID NO 146 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 146ggcagagaac cagaggccgg aggagactgc ctctttacag ccagg    #                  #45 <210> SEQ ID NO 147 <211> LENGTH: 1686 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 147ctcctcttaa catacttgca gctaaaacta aatattgctg cttggggacc tc#cttctagc     60cttaaatttc agctcatcac cttcacctgc cttggtcatg gctctgctat tc#tccttgat    120ccttgccatt tgcaccagac ctggattcct agcgtctcca tctggagtgc gg#ctggtggg    180gggcctccac cgctgtgaag ggcgggtgga ggtggaacag aaaggccagt gg#ggcaccgt    240gtgtgatgac ggctgggaca ttaaggacgt ggctgtgttg tgccgggagc tg#ggctgtgg    300agctgccagc ggaaccccta gtggtatttt gtatgagcca ccagcagaaa aa#gagcaaaa    360ggtcctcatc caatcagtca gttgcacagg aacagaagat acattggctc ag#tgtgagca    420agaagaagtt tatgattgtt cacatgatga agatgctggg gcatcgtgtg ag#aacccaga    480gagctctttc tccccagtcc cagagggtgt caggctggct gacggccctg gg#cattgcaa    540gggacgcgtg gaagtgaagc accagaacca gtggtatacc gtgtgccaga ca#ggctggag    600cctccgggcc gcaaaggtgg tgtgccggca gctgggatgt gggagggctg ta#ctgactca    660aaaacgctgc aacaagcatg cctatggccg aaaacccatc tggctgagcc ag#atgtcatg    720ctcaggacga gaagcaaccc ttcaggattg cccttctggg ccttggggga ag#aacacctg    780caaccatgat gaagacacgt gggtcgaatg tgaagatccc tttgacttga ga#ctagtagg    840aggagacaac ctctgctctg ggcgactgga ggtgctgcac aagggcgtat gg#ggctctgt    900ctgtgatgac aactggggag aaaaggagga ccaggtggta tgcaagcaac tg#ggctgtgg    960gaagtccctc tctccctcct tcagagaccg gaaatgctat ggccctgggg tt#ggccgcat   1020ctggctggat aatgttcgtt gctcagggga ggagcagtcc ctggagcagt gc#cagcacag   1080attttggggg tttcacgact gcacccacca ggaagatgtg gctgtcatct gc#tcagtgta   1140ggtgggcatc atctaatctg ttgagtgcct gaatagaaga aaaacacaga ag#aagggagc   1200atttactgtc tacatgactg catgggatga acactgatct tcttctgccc tt#ggactggg   1260acttatactt ggtgcccctg attctcaggc cttcagagtt ggatcagaac tt#acaacatc   1320aggtctagtt ctcaggccat cagacatagt ttggaactac atcaccacct tt#cctatgtc   1380tccacattgc acacagcaga ttcccagcct ccataattgt gtgtatcaac ta#cttaaata   1440cattctcaca cacacacaca cacacacaca cacacacaca cacacataca cc#atttgtcc   1500tgtttctctg aagaactctg acaaaataca gattttggta ctgaaagaga tt#ctagagga   1560acggaatttt aaggataaat tttctgaatt ggttatgggg tttctgaaat tg#gctctata   1620atctaattag atataaaatt ctggtaactt tatttacaat aataaagata gc#actatgtg   1680 ttcaaa                  #                  #                   #         1686 <210> SEQ ID NO 148 <211> LENGTH: 347<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 148Met Ala Leu Leu Phe Ser Leu Ile Leu Ala Il #e Cys Thr Arg Pro Gly  1               5  #                 10  #                 15Phe Leu Ala Ser Pro Ser Gly Val Arg Leu Va #l Gly Gly Leu His Arg             20      #             25      #             30Cys Glu Gly Arg Val Glu Val Glu Gln Lys Gl #y Gln Trp Gly Thr Val         35          #         40          #         45Cys Asp Asp Gly Trp Asp Ile Lys Asp Val Al #a Val Leu Cys Arg Glu     50              #     55              #     60Leu Gly Cys Gly Ala Ala Ser Gly Thr Pro Se #r Gly Ile Leu Tyr Glu 65                  # 70                  # 75                  # 80Pro Pro Ala Glu Lys Glu Gln Lys Val Leu Il #e Gln Ser Val Ser Cys                 85  #                 90  #                 95Thr Gly Thr Glu Asp Thr Leu Ala Gln Cys Gl #u Gln Glu Glu Val Tyr            100       #           105       #           110Asp Cys Ser His Asp Glu Asp Ala Gly Ala Se #r Cys Glu Asn Pro Glu        115           #       120           #       125Ser Ser Phe Ser Pro Val Pro Glu Gly Val Ar #g Leu Ala Asp Gly Pro    130               #   135               #   140Gly His Cys Lys Gly Arg Val Glu Val Lys Hi #s Gln Asn Gln Trp Tyr145                 1 #50                 1 #55                 1 #60Thr Val Cys Gln Thr Gly Trp Ser Leu Arg Al #a Ala Lys Val Val Cys                165   #               170   #               175Arg Gln Leu Gly Cys Gly Arg Ala Val Leu Th #r Gln Lys Arg Cys Asn            180       #           185       #           190Lys His Ala Tyr Gly Arg Lys Pro Ile Trp Le #u Ser Gln Met Ser Cys        195           #       200           #       205Ser Gly Arg Glu Ala Thr Leu Gln Asp Cys Pr #o Ser Gly Pro Trp Gly    210               #   215               #   220Lys Asn Thr Cys Asn His Asp Glu Asp Thr Tr #p Val Glu Cys Glu Asp225                 2 #30                 2 #35                 2 #40Pro Phe Asp Leu Arg Leu Val Gly Gly Asp As #n Leu Cys Ser Gly Arg                245   #               250   #               255Leu Glu Val Leu His Lys Gly Val Trp Gly Se #r Val Cys Asp Asp Asn            260       #           265       #           270Trp Gly Glu Lys Glu Asp Gln Val Val Cys Ly #s Gln Leu Gly Cys Gly        275           #       280           #       285Lys Ser Leu Ser Pro Ser Phe Arg Asp Arg Ly #s Cys Tyr Gly Pro Gly    290               #   295               #   300Val Gly Arg Ile Trp Leu Asp Asn Val Arg Cy #s Ser Gly Glu Glu Gln305                 3 #10                 3 #15                 3 #20Ser Leu Glu Gln Cys Gln His Arg Phe Trp Gl #y Phe His Asp Cys Thr                325   #               330   #               335His Gln Glu Asp Val Ala Val Ile Cys Ser Va #l             340      #           345 <210> SEQ ID NO 149 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 149ttcagctcat caccttcacc tgcc           #                  #                24 <210> SEQ ID NO 150 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 150ggctcataca aaataccact aggg           #                  #                24 <210> SEQ ID NO 151 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 151gggcctccac cgctgtgaag ggcgggtgga ggtggaacag aaaggccagt  #              50 <210> SEQ ID NO 152 <211> LENGTH: 1427 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 152actgcactcg gttctatcga ttgaattccc cggggatcct ctagagatcc ct#cgacctcg     60acccacgcgt ccgcggacgc gtgggcggac gcgtgggccg gctaccagga ag#agtctgcc    120gaaggtgaag gccatggact tcatcacctc cacagccatc ctgcccctgc tg#ttcggctg    180cctgggcgtc ttcggcctct tccggctgct gcagtgggtg cgcgggaagg cc#tacctgcg    240gaatgctgtg gtggtgatca caggcgccac ctcagggctg ggcaaagaat gt#gcaaaagt    300cttctatgct gcgggtgcta aactggtgct ctgtggccgg aatggtgggg cc#ctagaaga    360gctcatcaga gaacttaccg cttctcatgc caccaaggtg cagacacaca ag#ccttactt    420ggtgaccttc gacctcacag actctggggc catagttgca gcagcagctg ag#atcctgca    480gtgctttggc tatgtcgaca tacttgtcaa caatgctggg atcagctacc gt#ggtaccat    540catggacacc acagtggatg tggacaagag ggtcatggag acaaactact tt#ggcccagt    600tgctctaacg aaagcactcc tgccctccat gatcaagagg aggcaaggcc ac#attgtcgc    660catcagcagc atccagggca agatgagcat tccttttcga tcagcatatg ca#gcctccaa    720gcacgcaacc caggctttct ttgactgtct gcgtgccgag atggaacagt at#gaaattga    780ggtgaccgtc atcagccccg gctacatcca caccaacctc tctgtaaatg cc#atcaccgc    840ggatggatct aggtatggag ttatggacac caccacagcc cagggccgaa gc#cctgtgga    900ggtggcccag gatgttcttg ctgctgtggg gaagaagaag aaagatgtga tc#ctggctga    960cttactgcct tccttggctg tttatcttcg aactctggct cctgggctct tc#ttcagcct   1020catggcctcc agggccagaa aagagcggaa atccaagaac tcctagtact ct#gaccagcc   1080agggccaggg cagagaagca gcactcttag gcttgcttac tctacaaggg ac#agttgcat   1140ttgttgagac tttaatggag atttgtctca caagtgggaa agactgaaga aa#cacatctc   1200gtgcagatct gctggcagag gacaatcaaa aacgacaaca agcttcttcc ca#gggtgagg   1260ggaaacactt aaggaataaa tatggagctg gggtttaaca ctaaaaacta ga#aataaaca   1320tctcaaacag taaaaaaaaa aaaaaagggc ggccgcgact ctagagtcga cc#tgcagaag   1380 cttggccgcc atggcccaac ttgtttattg cagcttataa tggttac   #              1427 <210> SEQ ID NO 153 <211> LENGTH: 310<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153Met Asp Phe Ile Thr Ser Thr Ala Ile Leu Pr #o Leu Leu Phe Gly Cys  1               5  #                 10  #                 15Leu Gly Val Phe Gly Leu Phe Arg Leu Leu Gl #n Trp Val Arg Gly Lys             20      #             25      #             30Ala Tyr Leu Arg Asn Ala Val Val Val Ile Th #r Gly Ala Thr Ser Gly         35          #         40          #         45Leu Gly Lys Glu Cys Ala Lys Val Phe Tyr Al #a Ala Gly Ala Lys Leu     50              #     55              #     60Val Leu Cys Gly Arg Asn Gly Gly Ala Leu Gl #u Glu Leu Ile Arg Glu 65                  # 70                  # 75                  # 80Leu Thr Ala Ser His Ala Thr Lys Val Gln Th #r His Lys Pro Tyr Leu                 85  #                 90  #                 95Val Thr Phe Asp Leu Thr Asp Ser Gly Ala Il #e Val Ala Ala Ala Ala            100       #           105       #           110Glu Ile Leu Gln Cys Phe Gly Tyr Val Asp Il #e Leu Val Asn Asn Ala        115           #       120           #       125Gly Ile Ser Tyr Arg Gly Thr Ile Met Asp Th #r Thr Val Asp Val Asp    130               #   135               #   140Lys Arg Val Met Glu Thr Asn Tyr Phe Gly Pr #o Val Ala Leu Thr Lys145                 1 #50                 1 #55                 1 #60Ala Leu Leu Pro Ser Met Ile Lys Arg Arg Gl #n Gly His Ile Val Ala                165   #               170   #               175Ile Ser Ser Ile Gln Gly Lys Met Ser Ile Pr #o Phe Arg Ser Ala Tyr            180       #           185       #           190Ala Ala Ser Lys His Ala Thr Gln Ala Phe Ph #e Asp Cys Leu Arg Ala        195           #       200           #       205Glu Met Glu Gln Tyr Glu Ile Glu Val Thr Va #l Ile Ser Pro Gly Tyr    210               #   215               #   220Ile His Thr Asn Leu Ser Val Asn Ala Ile Th #r Ala Asp Gly Ser Arg225                 2 #30                 2 #35                 2 #40Tyr Gly Val Met Asp Thr Thr Thr Ala Gln Gl #y Arg Ser Pro Val Glu                245   #               250   #               255Val Ala Gln Asp Val Leu Ala Ala Val Gly Ly #s Lys Lys Lys Asp Val            260       #           265       #           270Ile Leu Ala Asp Leu Leu Pro Ser Leu Ala Va #l Tyr Leu Arg Thr Leu        275           #       280           #       285Ala Pro Gly Leu Phe Phe Ser Leu Met Ala Se #r Arg Ala Arg Lys Glu    290               #   295               #   300Arg Lys Ser Lys Asn Ser 305                 3 #10 <210> SEQ ID NO 154<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 154ggtgctaaac tggtgctctg tggc           #                  #                24 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 155cagggcaaga tgagcattcc             #                  #                   # 20 <210> SEQ ID NO 156 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 156tcatactgtt ccatctcggc acgc           #                  #                24 <210> SEQ ID NO 157 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 157aatggtgggg ccctagaaga gctcatcaga gaactcaccg cttctcatgc  #              50 <210> SEQ ID NO 158 <211> LENGTH: 1771 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 158cccacgcgtc cgctggtgtt agatcgagca accctctaaa agcagtttag ag#tggtaaaa     60aaaaaaaaaa acacaccaaa cgctcgcagc cacaaaaggg atgaaatttc tt#ctggacat    120cctcctgctt ctcccgttac tgatcgtctg ctccctagag tccttcgtga ag#ctttttat    180tcctaagagg agaaaatcag tcaccggcga aatcgtgctg attacaggag ct#gggcatgg    240aattgggaga ctgactgcct atgaatttgc taaacttaaa agcaagctgg tt#ctctggga    300tataaataag catggactgg aggaaacagc tgccaaatgc aagggactgg gt#gccaaggt    360tcataccttt gtggtagact gcagcaaccg agaagatatt tacagctctg ca#aagaaggt    420gaaggcagaa attggagatg ttagtatttt agtaaataat gctggtgtag tc#tatacatc    480agatttgttt gctacacaag atcctcagat tgaaaagact tttgaagtta at#gtacttgc    540acatttctgg actacaaagg catttcttcc tgcaatgacg aagaataacc at#ggccatat    600tgtcactgtg gcttcggcag ctggacatgt ctcggtcccc ttcttactgg ct#tactgttc    660aagcaagttt gctgctgttg gatttcataa aactttgaca gatgaactgg ct#gccttaca    720aataactgga gtcaaaacaa catgtctgtg tcctaatttc gtaaacactg gc#ttcatcaa    780aaatccaagt acaagtttgg gacccactct ggaacctgag gaagtggtaa ac#aggctgat    840gcatgggatt ctgactgagc agaagatgat ttttattcca tcttctatag ct#tttttaac    900aacattggaa aggatccttc ctgagcgttt cctggcagtt ttaaaacgaa aa#atcagtgt    960taagtttgat gcagttattg gatataaaat gaaagcgcaa taagcaccta gt#tttctgaa   1020aactgattta ccaggtttag gttgatgtca tctaatagtg ccagaatttt aa#tgtttgaa   1080cttctgtttt ttctaattat ccccatttct tcaatatcat ttttgaggct tt#ggcagtct   1140tcatttacta ccacttgttc tttagccaaa agctgattac atatgatata aa#cagagaaa   1200tacctttaga ggtgacttta aggaaaatga agaaaaagaa ccaaaatgac tt#tattaaaa   1260taatttccaa gattatttgt ggctcacctg aaggctttgc aaaatttgta cc#ataaccgt   1320ttatttaaca tatattttta tttttgattg cacttaaatt ttgtataatt tg#tgtttctt   1380tttctgttct acataaaatc agaaacttca agctctctaa ataaaatgaa gg#actatatc   1440tagtggtatt tcacaatgaa tatcatgaac tctcaatggg taggtttcat cc#tacccatt   1500gccactctgt ttcctgagag atacctcaca ttccaatgcc aaacatttct gc#acagggaa   1560gctagaggtg gatacacgtg ttgcaagtat aaaagcatca ctgggattta ag#gagaattg   1620agagaatgta cccacaaatg gcagcaataa taaatggatc acacttaaaa aa#aaaaaaaa   1680aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa#aaaaaaaa   1740 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a        #                   #        1771 <210> SEQ ID NO 159 <211> LENGTH: 300<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 159Met Lys Phe Leu Leu Asp Ile Leu Leu Leu Le #u Pro Leu Leu Ile Val  1               5  #                 10  #                 15Cys Ser Leu Glu Ser Phe Val Lys Leu Phe Il #e Pro Lys Arg Arg Lys             20      #             25      #             30Ser Val Thr Gly Glu Ile Val Leu Ile Thr Gl #y Ala Gly His Gly Ile         35          #         40          #         45Gly Arg Leu Thr Ala Tyr Glu Phe Ala Lys Le #u Lys Ser Lys Leu Val     50              #     55              #     60Leu Trp Asp Ile Asn Lys His Gly Leu Glu Gl #u Thr Ala Ala Lys Cys 65                  # 70                  # 75                  # 80Lys Gly Leu Gly Ala Lys Val His Thr Phe Va #l Val Asp Cys Ser Asn                 85  #                 90  #                 95Arg Glu Asp Ile Tyr Ser Ser Ala Lys Lys Va #l Lys Ala Glu Ile Gly            100       #           105       #           110Asp Val Ser Ile Leu Val Asn Asn Ala Gly Va #l Val Tyr Thr Ser Asp        115           #       120           #       125Leu Phe Ala Thr Gln Asp Pro Gln Ile Glu Ly #s Thr Phe Glu Val Asn    130               #   135               #   140Val Leu Ala His Phe Trp Thr Thr Lys Ala Ph #e Leu Pro Ala Met Thr145                 1 #50                 1 #55                 1 #60Lys Asn Asn His Gly His Ile Val Thr Val Al #a Ser Ala Ala Gly His                165   #               170   #               175Val Ser Val Pro Phe Leu Leu Ala Tyr Cys Se #r Ser Lys Phe Ala Ala            180       #           185       #           190Val Gly Phe His Lys Thr Leu Thr Asp Glu Le #u Ala Ala Leu Gln Ile        195           #       200           #       205Thr Gly Val Lys Thr Thr Cys Leu Cys Pro As #n Phe Val Asn Thr Gly    210               #   215               #   220Phe Ile Lys Asn Pro Ser Thr Ser Leu Gly Pr #o Thr Leu Glu Pro Glu225                 2 #30                 2 #35                 2 #40Glu Val Val Asn Arg Leu Met His Gly Ile Le #u Thr Glu Gln Lys Met                245   #               250   #               255Ile Phe Ile Pro Ser Ser Ile Ala Phe Leu Th #r Thr Leu Glu Arg Ile            260       #           265       #           270Leu Pro Glu Arg Phe Leu Ala Val Leu Lys Ar #g Lys Ile Ser Val Lys        275           #       280           #       285Phe Asp Ala Val Ile Gly Tyr Lys Met Lys Al #a Gln     290              #   295               #   300 <210> SEQ ID NO 160 <211> LENGTH: 23<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 160ggtgaaggca gaaattggag atg            #                  #                23 <210> SEQ ID NO 161 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 161atcccatgca tcagcctgtt tacc           #                  #                24 <210> SEQ ID NO 162 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 162gctggtgtag tctatacatc agatttgttt gctacacaag atcctcag  #                48 <210> SEQ ID NO 163 <211> LENGTH: 2076<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 163cccacgcgtc cgcggacgcg tgggtcgact agttctagat cgcgagcggc cg#cccgcggc     60tcagggagga gcaccgactg cgccgcaccc tgagagatgg ttggtgccat gt#ggaaggtg    120attgtttcgc tggtcctgtt gatgcctggc ccctgtgatg ggctgtttcg ct#ccctatac    180agaagtgttt ccatgccacc taagggagac tcaggacagc cattatttct ca#ccccttac    240attgaagctg ggaagatcca aaaaggaaga gaattgagtt tggtcggccc tt#tcccagga    300ctgaacatga agagttatgc cggcttcctc accgtgaata agacttacaa ca#gcaacctc    360ttcttctggt tcttcccagc tcagatacag ccagaagatg ccccagtagt tc#tctggcta    420cagggtgggc cgggaggttc atccatgttt ggactctttg tggaacatgg gc#cttatgtt    480gtcacaagta acatgacctt gcgtgacaga gacttcccct ggaccacaac gc#tctccatg    540ctttacattg acaatccagt gggcacaggc ttcagtttta ctgatgatac cc#acggatat    600gcagtcaatg aggacgatgt agcacgggat ttatacagtg cactaattca gt#ttttccag    660atatttcctg aatataaaaa taatgacttt tatgtcactg gggagtctta tg#cagggaaa    720tatgtgccag ccattgcaca cctcatccat tccctcaacc ctgtgagaga gg#tgaagatc    780aacctgaacg gaattgctat tggagatgga tattctgatc ccgaatcaat ta#tagggggc    840tatgcagaat tcctgtacca aattggcttg ttggatgaga agcaaaaaaa gt#acttccag    900aagcagtgcc atgaatgcat agaacacatc aggaagcaga actggtttga gg#cctttgaa    960atactggata aactactaga tggcgactta acaagtgatc cttcttactt cc#agaatgtt   1020acaggatgta gtaattacta taactttttg cggtgcacgg aacctgagga tc#agctttac   1080tatgtgaaat ttttgtcact cccagaggtg agacaagcca tccacgtggg ga#atcagact   1140tttaatgatg gaactatagt tgaaaagtac ttgcgagaag atacagtaca gt#cagttaag   1200ccatggttaa ctgaaatcat gaataattat aaggttctga tctacaatgg cc#aactggac   1260atcatcgtgg cagctgccct gacagagcgc tccttgatgg gcatggactg ga#aaggatcc   1320caggaataca agaaggcaga aaaaaaagtt tggaagatct ttaaatctga ca#gtgaagtg   1380gctggttaca tccggcaagc gggtgacttc catcaggtaa ttattcgagg tg#gaggacat   1440attttaccct atgaccagcc tctgagagct tttgacatga ttaatcgatt ca#tttatgga   1500aaaggatggg atccttatgt tggataaact accttcccaa aagagaacat ca#gaggtttt   1560cattgctgaa aagaaaatcg taaaaacaga aaatgtcata ggaataaaaa aa#ttatcttt   1620tcatatctgc aagatttttt tcatcaataa aaattatcct tgaaacaagt ga#gcttttgt   1680ttttgggggg agatgtttac tacaaaatta acatgagtac atgagtaaga at#tacattat   1740ttaacttaaa ggatgaaagg tatggatgat gtgacactga gacaagatgt at#aaatgaaa   1800ttttagggtc ttgaatagga agttttaatt tcttctaaga gtaagtgaaa ag#tgcagttg   1860taacaaacaa agctgtaaca tctttttctg ccaataacag aagtttggca tg#ccgtgaag   1920gtgtttggaa atattattgg ataagaatag ctcaattatc ccaaataaat gg#atgaagct   1980ataatagttt tggggaaaag attctcaaat gtataaagtc ttagaacaaa ag#aattcttt   2040 gaaataaaaa tattatatat aaaagtaaaa aaaaaa      #                   #     2076 <210> SEQ ID NO 164 <211> LENGTH: 476<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 164Met Val Gly Ala Met Trp Lys Val Ile Val Se #r Leu Val Leu Leu Met  1               5  #                 10  #                 15Pro Gly Pro Cys Asp Gly Leu Phe Arg Ser Le #u Tyr Arg Ser Val Ser             20      #             25      #             30Met Pro Pro Lys Gly Asp Ser Gly Gln Pro Le #u Phe Leu Thr Pro Tyr         35          #         40          #         45Ile Glu Ala Gly Lys Ile Gln Lys Gly Arg Gl #u Leu Ser Leu Val Gly     50              #     55              #     60Pro Phe Pro Gly Leu Asn Met Lys Ser Tyr Al #a Gly Phe Leu Thr Val 65                  # 70                  # 75                  # 80Asn Lys Thr Tyr Asn Ser Asn Leu Phe Phe Tr #p Phe Phe Pro Ala Gln                 85  #                 90  #                 95Ile Gln Pro Glu Asp Ala Pro Val Val Leu Tr #p Leu Gln Gly Gly Pro            100       #           105       #           110Gly Gly Ser Ser Met Phe Gly Leu Phe Val Gl #u His Gly Pro Tyr Val        115           #       120           #       125Val Thr Ser Asn Met Thr Leu Arg Asp Arg As #p Phe Pro Trp Thr Thr    130               #   135               #   140Thr Leu Ser Met Leu Tyr Ile Asp Asn Pro Va #l Gly Thr Gly Phe Ser145                 1 #50                 1 #55                 1 #60Phe Thr Asp Asp Thr His Gly Tyr Ala Val As #n Glu Asp Asp Val Ala                165   #               170   #               175Arg Asp Leu Tyr Ser Ala Leu Ile Gln Phe Ph #e Gln Ile Phe Pro Glu            180       #           185       #           190Tyr Lys Asn Asn Asp Phe Tyr Val Thr Gly Gl #u Ser Tyr Ala Gly Lys        195           #       200           #       205Tyr Val Pro Ala Ile Ala His Leu Ile His Se #r Leu Asn Pro Val Arg    210               #   215               #   220Glu Val Lys Ile Asn Leu Asn Gly Ile Ala Il #e Gly Asp Gly Tyr Ser225                 2 #30                 2 #35                 2 #40Asp Pro Glu Ser Ile Ile Gly Gly Tyr Ala Gl #u Phe Leu Tyr Gln Ile                245   #               250   #               255Gly Leu Leu Asp Glu Lys Gln Lys Lys Tyr Ph #e Gln Lys Gln Cys His            260       #           265       #           270Glu Cys Ile Glu His Ile Arg Lys Gln Asn Tr #p Phe Glu Ala Phe Glu        275           #       280           #       285Ile Leu Asp Lys Leu Leu Asp Gly Asp Leu Th #r Ser Asp Pro Ser Tyr    290               #   295               #   300Phe Gln Asn Val Thr Gly Cys Ser Asn Tyr Ty #r Asn Phe Leu Arg Cys305                 3 #10                 3 #15                 3 #20Thr Glu Pro Glu Asp Gln Leu Tyr Tyr Val Ly #s Phe Leu Ser Leu Pro                325   #               330   #               335Glu Val Arg Gln Ala Ile His Val Gly Asn Gl #n Thr Phe Asn Asp Gly            340       #           345       #           350Thr Ile Val Glu Lys Tyr Leu Arg Glu Asp Th #r Val Gln Ser Val Lys        355           #       360           #       365Pro Trp Leu Thr Glu Ile Met Asn Asn Tyr Ly #s Val Leu Ile Tyr Asn    370               #   375               #   380Gly Gln Leu Asp Ile Ile Val Ala Ala Ala Le #u Thr Glu Arg Ser Leu385                 3 #90                 3 #95                 4 #00Met Gly Met Asp Trp Lys Gly Ser Gln Glu Ty #r Lys Lys Ala Glu Lys                405   #               410   #               415Lys Val Trp Lys Ile Phe Lys Ser Asp Ser Gl #u Val Ala Gly Tyr Ile            420       #           425       #           430Arg Gln Ala Gly Asp Phe His Gln Val Ile Il #e Arg Gly Gly Gly His        435           #       440           #       445Ile Leu Pro Tyr Asp Gln Pro Leu Arg Ala Ph #e Asp Met Ile Asn Arg    450               #   455               #   460Phe Ile Tyr Gly Lys Gly Trp Asp Pro Tyr Va #l Gly 465                 4#70                 4 #75 <210> SEQ ID NO 165 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 165ttccatgcca cctaagggag actc           #                  #                24 <210> SEQ ID NO 166 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 166tggatgaggt gtgcaatggc tggc           #                  #                24 <210> SEQ ID NO 167 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 167agctctcaga ggctggtcat aggg           #                  #                24 <210> SEQ ID NO 168 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 168gtcggccctt tcccaggact gaacatgaag agttatgccg gcttcctcac  #              50 <210> SEQ ID NO 169 <211> LENGTH: 2477 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 169cgagggcttt tccggctccg gaatggcaca tgtgggaatc ccagtcttgt tg#gctacaac     60atttttccct ttcctaacaa gttctaacag ctgttctaac agctagtgat ca#ggggttct    120tcttgctgga gaagaaaggg ctgagggcag agcagggcac tctcactcag gg#tgaccagc    180tccttgcctc tctgtggata acagagcatg agaaagtgaa gagatgcagc gg#agtgaggt    240gatggaagtc taaaatagga aggaattttg tgtgcaatat cagactctgg ga#gcagttga    300cctggagagc ctgggggagg gcctgcctaa caagctttca aaaaacagga gc#gacttcca    360ctgggctggg ataagacgtg ccggtaggat agggaagact gggtttagtc ct#aatatcaa    420attgactggc tgggtgaact tcaacagcct tttaacctct ctgggagatg aa#aacgatgg    480cttaaggggc cagaaataga gatgctttgt aaaataaaat tttaaaaaaa gc#aagtattt    540tatagcataa aggctagaga ccaaaataga taacaggatt ccctgaacat tc#ctaagagg    600gagaaagtat gttaaaaata gaaaaaccaa aatgcagaag gaggagactc ac#agagctaa    660accaggatgg ggaccctggg tcaggccagc ctctttgctc ctcccggaaa tt#atttttgg    720tctgaccact ctgccttgtg ttttgcagaa tcatgtgagg gccaaccggg ga#aggtggag    780cagatgagca cacacaggag ccgtctcctc accgccgccc ctctcagcat gg#aacagagg    840cagccctggc cccgggccct ggaggtggac agccgctctg tggtcctgct ct#cagtggtc    900tgggtgctgc tggccccccc agcagccggc atgcctcagt tcagcacctt cc#actctgag    960aatcgtgact ggaccttcaa ccacttgacc gtccaccaag ggacgggggc cg#tctatgtg   1020ggggccatca accgggtcta taagctgaca ggcaacctga ccatccaggt gg#ctcataag   1080acagggccag aagaggacaa caagtctcgt tacccgcccc tcatcgtgca gc#cctgcagc   1140gaagtgctca ccctcaccaa caatgtcaac aagctgctca tcattgacta ct#ctgagaac   1200cgcctgctgg cctgtgggag cctctaccag ggggtctgca agctgctgcg gc#tggatgac   1260ctcttcatcc tggtggagcc atcccacaag aaggagcact acctgtccag tg#tcaacaag   1320acgggcacca tgtacggggt gattgtgcgc tctgagggtg aggatggcaa gc#tcttcatc   1380ggcacggctg tggatgggaa gcaggattac ttcccgaccc tgtccagccg ga#agctgccc   1440cgagaccctg agtcctcagc catgctcgac tatgagctac acagcgattt tg#tctcctct   1500ctcatcaaga tcccttcaga caccctggcc ctggtctccc actttgacat ct#tctacatc   1560tacggctttg ctagtggggg ctttgtctac tttctcactg tccagcccga ga#cccctgag   1620ggtgtggcca tcaactccgc tggagacctc ttctacacct cacgcatcgt gc#ggctctgc   1680aaggatgacc ccaagttcca ctcatacgtg tccctgccct tcggctgcac cc#gggccggg   1740gtggaatacc gcctcctgca ggctgcttac ctggccaagc ctggggactc ac#tggcccag   1800gccttcaata tcaccagcca ggacgatgta ctctttgcca tcttctccaa ag#ggcagaag   1860cagtatcacc acccgcccga tgactctgcc ctgtgtgcct tccctatccg gg#ccatcaac   1920ttgcagatca aggagcgcct gcagtcctgc taccagggcg agggcaacct gg#agctcaac   1980tggctgctgg ggaaggacgt ccagtgcacg aaggcgcctg tccccatcga tg#ataacttc   2040tgtggactgg acatcaacca gcccctggga ggctcaactc cagtggaggg cc#tgaccctg   2100tacaccacca gcagggaccg catgacctct gtggcctcct acgtttacaa cg#gctacagc   2160gtggtttttg tggggactaa gagtggcaag ctgaaaaagg taagagtcta tg#agttcaga   2220tgctccaatg ccattcacct cctcagcaaa gagtccctct tggaaggtag ct#attggtgg   2280agatttaact ataggcaact ttattttctt ggggaacaaa ggtgaaatgg gg#aggtaaga   2340aggggttaat tttgtgactt agcttctagc tacttcctcc agccatcagt ca#ttgggtat   2400gtaaggaatg caagcgtatt tcaatatttc ccaaacttta agaaaaaact tt#aagaaggt   2460 acatctgcaa aagcaaa              #                  #                   # 2477 <210> SEQ ID NO 170 <211> LENGTH: 552<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 170Met Gly Thr Leu Gly Gln Ala Ser Leu Phe Al #a Pro Pro Gly Asn Tyr  1               5  #                 10  #                 15Phe Trp Ser Asp His Ser Ala Leu Cys Phe Al #a Glu Ser Cys Glu Gly             20      #             25      #             30Gln Pro Gly Lys Val Glu Gln Met Ser Thr Hi #s Arg Ser Arg Leu Leu         35          #         40          #         45Thr Ala Ala Pro Leu Ser Met Glu Gln Arg Gl #n Pro Trp Pro Arg Ala     50              #     55              #     60Leu Glu Val Asp Ser Arg Ser Val Val Leu Le #u Ser Val Val Trp Val 65                  # 70                  # 75                  # 80Leu Leu Ala Pro Pro Ala Ala Gly Met Pro Gl #n Phe Ser Thr Phe His                 85  #                 90  #                 95Ser Glu Asn Arg Asp Trp Thr Phe Asn His Le #u Thr Val His Gln Gly            100       #           105       #           110Thr Gly Ala Val Tyr Val Gly Ala Ile Asn Ar #g Val Tyr Lys Leu Thr        115           #       120           #       125Gly Asn Leu Thr Ile Gln Val Ala His Lys Th #r Gly Pro Glu Glu Asp    130               #   135               #   140Asn Lys Ser Arg Tyr Pro Pro Leu Ile Val Gl #n Pro Cys Ser Glu Val145                 1 #50                 1 #55                 1 #60Leu Thr Leu Thr Asn Asn Val Asn Lys Leu Le #u Ile Ile Asp Tyr Ser                165   #               170   #               175Glu Asn Arg Leu Leu Ala Cys Gly Ser Leu Ty #r Gln Gly Val Cys Lys            180       #           185       #           190Leu Leu Arg Leu Asp Asp Leu Phe Ile Leu Va #l Glu Pro Ser His Lys        195           #       200           #       205Lys Glu His Tyr Leu Ser Ser Val Asn Lys Th #r Gly Thr Met Tyr Gly    210               #   215               #   220Val Ile Val Arg Ser Glu Gly Glu Asp Gly Ly #s Leu Phe Ile Gly Thr225                 2 #30                 2 #35                 2 #40Ala Val Asp Gly Lys Gln Asp Tyr Phe Pro Th #r Leu Ser Ser Arg Lys                245   #               250   #               255Leu Pro Arg Asp Pro Glu Ser Ser Ala Met Le #u Asp Tyr Glu Leu His            260       #           265       #           270Ser Asp Phe Val Ser Ser Leu Ile Lys Ile Pr #o Ser Asp Thr Leu Ala        275           #       280           #       285Leu Val Ser His Phe Asp Ile Phe Tyr Ile Ty #r Gly Phe Ala Ser Gly    290               #   295               #   300Gly Phe Val Tyr Phe Leu Thr Val Gln Pro Gl #u Thr Pro Glu Gly Val305                 3 #10                 3 #15                 3 #20Ala Ile Asn Ser Ala Gly Asp Leu Phe Tyr Th #r Ser Arg Ile Val Arg                325   #               330   #               335Leu Cys Lys Asp Asp Pro Lys Phe His Ser Ty #r Val Ser Leu Pro Phe            340       #           345       #           350Gly Cys Thr Arg Ala Gly Val Glu Tyr Arg Le #u Leu Gln Ala Ala Tyr        355           #       360           #       365Leu Ala Lys Pro Gly Asp Ser Leu Ala Gln Al #a Phe Asn Ile Thr Ser    370               #   375               #   380Gln Asp Asp Val Leu Phe Ala Ile Phe Ser Ly #s Gly Gln Lys Gln Tyr385                 3 #90                 3 #95                 4 #00His His Pro Pro Asp Asp Ser Ala Leu Cys Al #a Phe Pro Ile Arg Ala                405   #               410   #               415Ile Asn Leu Gln Ile Lys Glu Arg Leu Gln Se #r Cys Tyr Gln Gly Glu            420       #           425       #           430Gly Asn Leu Glu Leu Asn Trp Leu Leu Gly Ly #s Asp Val Gln Cys Thr        435           #       440           #       445Lys Ala Pro Val Pro Ile Asp Asp Asn Phe Cy #s Gly Leu Asp Ile Asn    450               #   455               #   460Gln Pro Leu Gly Gly Ser Thr Pro Val Glu Gl #y Leu Thr Leu Tyr Thr465                 4 #70                 4 #75                 4 #80Thr Ser Arg Asp Arg Met Thr Ser Val Ala Se #r Tyr Val Tyr Asn Gly                485   #               490   #               495Tyr Ser Val Val Phe Val Gly Thr Lys Ser Gl #y Lys Leu Lys Lys Val            500       #           505       #           510Arg Val Tyr Glu Phe Arg Cys Ser Asn Ala Il #e His Leu Leu Ser Lys        515           #       520           #       525Glu Ser Leu Leu Glu Gly Ser Tyr Trp Trp Ar #g Phe Asn Tyr Arg Gln    530               #   535               #   540Leu Tyr Phe Leu Gly Glu Gln Arg 545                 5 #50<210> SEQ ID NO 171 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 171tggaataccg cctcctgcag             #                  #                   # 20 <210> SEQ ID NO 172 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 172cttctgccct ttggagaaga tggc           #                  #                24 <210> SEQ ID NO 173 <211> LENGTH: 43 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 173ggactcactg gcccaggcct tcaatatcac cagccaggac gat     #                  # 43 <210> SEQ ID NO 174 <211> LENGTH: 3106 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (1683)<223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 174aggctcccgc gcgcggctga gtgcggactg gagtgggaac ccgggtcccc gc#gcttagag     60aacacgcgat gaccacgtgg agcctccggc ggaggccggc ccgcacgctg gg#actcctgc    120tgctggtcgt cttgggcttc ctggtgctcc gcaggctgga ctggagcacc ct#ggtccctc    180tgcggctccg ccatcgacag ctggggctgc aggccaaggg ctggaacttc at#gctggagg    240attccacctt ctggatcttc gggggctcca tccactattt ccgtgtgccc ag#ggagtact    300ggagggaccg cctgctgaag atgaaggcct gtggcttgaa caccctcacc ac#ctatgttc    360cgtggaacct gcatgagcca gaaagaggca aatttgactt ctctgggaac ct#ggacctgg    420aggccttcgt cctgatggcc gcagagatcg ggctgtgggt gattctgcgt cc#aggcccct    480acatctgcag tgagatggac ctcgggggct tgcccagctg gctactccaa ga#ccctggca    540tgaggctgag gacaacttac aagggcttca ccgaagcagt ggacctttat tt#tgaccacc    600tgatgtccag ggtggtgcca ctccagtaca agcgtggggg acctatcatt gc#cgtgcagg    660tggagaatga atatggttcc tataataaag accccgcata catgccctac gt#caagaagg    720cactggagga ccgtggcatt gtggaactgc tcctgacttc agacaacaag ga#tgggctga    780gcaaggggat tgtccaggga gtcttggcca ccatcaactt gcagtcaaca ca#cgagctgc    840agctactgac cacctttctc ttcaacgtcc aggggactca gcccaagatg gt#gatggagt    900actggacggg gtggtttgac tcgtggggag gccctcacaa tatcttggat tc#ttctgagg    960ttttgaaaac cgtgtctgcc attgtggacg ccggctcctc catcaacctc ta#catgttcc   1020acggaggcac caactttggc ttcatgaatg gagccatgca cttccatgac ta#caagtcag   1080atgtcaccag ctatgactat gatgctgtgc tgacagaagc cggcgattac ac#ggccaagt   1140acatgaagct tcgagacttc ttcggctcca tctcaggcat ccctctccct cc#cccacctg   1200accttcttcc caagatgccg tatgagccct taacgccagt cttgtacctg tc#tctgtggg   1260acgccctcaa gtacctgggg gagccaatca agtctgaaaa gcccatcaac at#ggagaacc   1320tgccagtcaa tgggggaaat ggacagtcct tcgggtacat tctctatgag ac#cagcatca   1380cctcgtctgg catcctcagt ggccacgtgc atgatcgggg gcaggtgttt gt#gaacacag   1440tatccatagg attcttggac tacaagacaa cgaagattgc tgtccccctg at#ccagggtt   1500acaccgtgct gaggatcttg gtggagaatc gtgggcgagt caactatggg ga#gaatattg   1560atgaccagcg caaaggctta attggaaatc tctatctgaa tgattcaccc ct#gaaaaact   1620tcagaatcta tagcctggat atgaagaaga gcttctttca gaggttcggc ct#ggacaaat   1680ggngttccct cccagaaaca cccacattac ctgctttctt cttgggtagc tt#gtccatca   1740gctccacgcc ttgtgacacc tttctgaagc tggagggctg ggagaagggg gt#tgtattca   1800tcaatggcca gaaccttgga cgttactgga acattggacc ccagaagacg ct#ttacctcc   1860caggtccctg gttgagcagc ggaatcaacc aggtcatcgt ttttgaggag ac#gatggcgg   1920gccctgcatt acagttcacg gaaacccccc acctgggcag gaaccagtac at#taagtgag   1980cggtggcacc ccctcctgct ggtgccagtg ggagactgcc gcctcctctt ga#cctgaagc   2040ctggtggctg ctgccccacc cctcactgca aaagcatctc cttaagtagc aa#cctcaggg   2100actgggggct acagtctgcc cctgtctcag ctcaaaaccc taagcctgca gg#gaaaggtg   2160ggatggctct gggcctggct ttgttgatga tggctttcct acagccctgc tc#ttgtgccg   2220aggctgtcgg gctgtctcta gggtgggagc agctaatcag atcgcccagc ct#ttggccct   2280cagaaaaagt gctgaaacgt gcccttgcac cggacgtcac agccctgcga gc#atctgctg   2340gactcaggcg tgctctttgc tggttcctgg gaggcttggc cacatccctc at#ggccccat   2400tttatccccg aaatcctggg tgtgtcacca gtgtagaggg tggggaaggg gt#gtctcacc   2460tgagctgact ttgttcttcc ttcacaacct tctgagcctt ctttgggatt ct#ggaaggaa   2520ctcggcgtga gaaacatgtg acttcccctt tcccttccca ctcgctgctt cc#cacagggt   2580gacaggctgg gctggagaaa cagaaatcct caccctgcgt cttcccaagt ta#gcaggtgt   2640ctctggtgtt cagtgaggag gacatgtgag tcctggcaga agccatggcc ca#tgtctgca   2700catccaggga ggaggacaga aggcccagct cacatgtgag tcctggcaga ag#ccatggcc   2760catgtctgca catccaggga ggaggacaga aggcccagct cacatgtgag tc#ctggcaga   2820agccatggcc catgtctgca catccaggga ggaggacaga aggcccagct ca#catgtgag   2880tcctggcaga agccatggcc catgtctgca catccaggga ggaggacaga ag#gcccagct   2940cagtggcccc cgctccccac cccccacgcc cgaacagcag gggcagagca gc#cctccttc   3000gaagtgtgtc caagtccgca tttgagcctt gttctggggc ccagcccaac ac#ctggcttg   3060 ggctcactgt cctgagttgc agtaaagcta taaccttgaa tcacaa   #               3106 <210> SEQ ID NO 175 <211> LENGTH: 636<212> TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: (539)<223> OTHER INFORMATION: Any amino acid <400> SEQUENCE: 175Met Thr Thr Trp Ser Leu Arg Arg Arg Pro Al #a Arg Thr Leu Gly Leu  1               5  #                 10  #                 15Leu Leu Leu Val Val Leu Gly Phe Leu Val Le #u Arg Arg Leu Asp Trp             20      #             25      #             30Ser Thr Leu Val Pro Leu Arg Leu Arg His Ar #g Gln Leu Gly Leu Gln         35          #         40          #         45Ala Lys Gly Trp Asn Phe Met Leu Glu Asp Se #r Thr Phe Trp Ile Phe     50              #     55              #     60Gly Gly Ser Ile His Tyr Phe Arg Val Pro Ar #g Glu Tyr Trp Arg Asp 65                  # 70                  # 75                  # 80Arg Leu Leu Lys Met Lys Ala Cys Gly Leu As #n Thr Leu Thr Thr Tyr                 85  #                 90  #                 95Val Pro Trp Asn Leu His Glu Pro Glu Arg Gl #y Lys Phe Asp Phe Ser            100       #           105       #           110Gly Asn Leu Asp Leu Glu Ala Phe Val Leu Me #t Ala Ala Glu Ile Gly        115           #       120           #       125Leu Trp Val Ile Leu Arg Pro Gly Pro Tyr Il #e Cys Ser Glu Met Asp    130               #   135               #   140Leu Gly Gly Leu Pro Ser Trp Leu Leu Gln As #p Pro Gly Met Arg Leu145                 1 #50                 1 #55                 1 #60Arg Thr Thr Tyr Lys Gly Phe Thr Glu Ala Va #l Asp Leu Tyr Phe Asp                165   #               170   #               175His Leu Met Ser Arg Val Val Pro Leu Gln Ty #r Lys Arg Gly Gly Pro            180       #           185       #           190Ile Ile Ala Val Gln Val Glu Asn Glu Tyr Gl #y Ser Tyr Asn Lys Asp        195           #       200           #       205Pro Ala Tyr Met Pro Tyr Val Lys Lys Ala Le #u Glu Asp Arg Gly Ile    210               #   215               #   220Val Glu Leu Leu Leu Thr Ser Asp Asn Lys As #p Gly Leu Ser Lys Gly225                 2 #30                 2 #35                 2 #40Ile Val Gln Gly Val Leu Ala Thr Ile Asn Le #u Gln Ser Thr His Glu                245   #               250   #               255Leu Gln Leu Leu Thr Thr Phe Leu Phe Asn Va #l Gln Gly Thr Gln Pro            260       #           265       #           270Lys Met Val Met Glu Tyr Trp Thr Gly Trp Ph #e Asp Ser Trp Gly Gly        275           #       280           #       285Pro His Asn Ile Leu Asp Ser Ser Glu Val Le #u Lys Thr Val Ser Ala    290               #   295               #   300Ile Val Asp Ala Gly Ser Ser Ile Asn Leu Ty #r Met Phe His Gly Gly305                 3 #10                 3 #15                 3 #20Thr Asn Phe Gly Phe Met Asn Gly Ala Met Hi #s Phe His Asp Tyr Lys                325   #               330   #               335Ser Asp Val Thr Ser Tyr Asp Tyr Asp Ala Va #l Leu Thr Glu Ala Gly            340       #           345       #           350Asp Tyr Thr Ala Lys Tyr Met Lys Leu Arg As #p Phe Phe Gly Ser Ile        355           #       360           #       365Ser Gly Ile Pro Leu Pro Pro Pro Pro Asp Le #u Leu Pro Lys Met Pro    370               #   375               #   380Tyr Glu Pro Leu Thr Pro Val Leu Tyr Leu Se #r Leu Trp Asp Ala Leu385                 3 #90                 3 #95                 4 #00Lys Tyr Leu Gly Glu Pro Ile Lys Ser Glu Ly #s Pro Ile Asn Met Glu                405   #               410   #               415Asn Leu Pro Val Asn Gly Gly Asn Gly Gln Se #r Phe Gly Tyr Ile Leu            420       #           425       #           430Tyr Glu Thr Ser Ile Thr Ser Ser Gly Ile Le #u Ser Gly His Val His        435           #       440           #       445Asp Arg Gly Gln Val Phe Val Asn Thr Val Se #r Ile Gly Phe Leu Asp    450               #   455               #   460Tyr Lys Thr Thr Lys Ile Ala Val Pro Leu Il #e Gln Gly Tyr Thr Val465                 4 #70                 4 #75                 4 #80Leu Arg Ile Leu Val Glu Asn Arg Gly Arg Va #l Asn Tyr Gly Glu Asn                485   #               490   #               495Ile Asp Asp Gln Arg Lys Gly Leu Ile Gly As #n Leu Tyr Leu Asn Asp            500       #           505       #           510Ser Pro Leu Lys Asn Phe Arg Ile Tyr Ser Le #u Asp Met Lys Lys Ser        515           #       520           #       525Phe Phe Gln Arg Phe Gly Leu Asp Lys Trp Xa #a Ser Leu Pro Glu Thr    530               #   535               #   540Pro Thr Leu Pro Ala Phe Phe Leu Gly Ser Le #u Ser Ile Ser Ser Thr545                 5 #50                 5 #55                 5 #60Pro Cys Asp Thr Phe Leu Lys Leu Glu Gly Tr #p Glu Lys Gly Val Val                565   #               570   #               575Phe Ile Asn Gly Gln Asn Leu Gly Arg Tyr Tr #p Asn Ile Gly Pro Gln            580       #           585       #           590Lys Thr Leu Tyr Leu Pro Gly Pro Trp Leu Se #r Ser Gly Ile Asn Gln        595           #       600           #       605Val Ile Val Phe Glu Glu Thr Met Ala Gly Pr #o Ala Leu Gln Phe Thr    610               #   615               #   620Glu Thr Pro His Leu Gly Arg Asn Gln Tyr Il #e Lys 625                 6#30                 6 #35 <210> SEQ ID NO 176 <211> LENGTH: 2505<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 176ggggacgcgg agctgagagg ctccgggcta gctaggtgta ggggtggacg gg#tcccagga     60ccctggtgag ggttctctac ttggccttcg gtgggggtca agacgcaggc ac#ctacgcca    120aaggggagca aagccgggct cggcccgagg cccccaggac ctccatctcc ca#atgttgga    180ggaatccgac acgtgacggt ctgtccgccg tctcagacta gaggagcgct gt#aaacgcca    240tggctcccaa gaagctgtcc tgccttcgtt ccctgctgct gccgctcagc ct#gacgctac    300tgctgcccca ggcagacact cggtcgttcg tagtggatag gggtcatgac cg#gtttctcc    360tagacggggc cccgttccgc tatgtgtctg gcagcctgca ctactttcgg gt#accgcggg    420tgctttgggc cgaccggctt ttgaagatgc gatggagcgg cctcaacgcc at#acagtttt    480atgtgccctg gaactaccac gagccacagc ctggggtcta taactttaat gg#cagccggg    540acctcattgc ctttctgaat gaggcagctc tagcgaacct gttggtcata ct#gagaccag    600gaccttacat ctgtgcagag tgggagatgg ggggtctccc atcctggttg ct#tcgaaaac    660ctgaaattca tctaagaacc tcagatccag acttccttgc cgcagtggac tc#ctggttca    720aggtcttgct gcccaagata tatccatggc tttatcacaa tgggggcaac at#cattagca    780ttcaggtgga gaatgaatat ggtagctaca gagcctgtga cttcagctac at#gaggcact    840tggctgggct cttccgtgca ctgctaggag aaaagatctt gctcttcacc ac#agatgggc    900ctgaaggact caagtgtggc tccctccggg gactctatac cactgtagat tt#tggcccag    960ctgacaacat gaccaaaatc tttaccctgc ttcggaagta tgaaccccat gg#gccattgg   1020taaactctga gtactacaca ggctggctgg attactgggg ccagaatcac tc#cacacggt   1080ctgtgtcagc tgtaaccaaa ggactagaga acatgctcaa gttgggagcc ag#tgtgaaca   1140tgtacatgtt ccatggaggt accaactttg gatattggaa tggtgccgat aa#gaagggac   1200gcttccttcc gattactacc agctatgact atgatgcacc tatatctgaa gc#aggggacc   1260ccacacctaa gctttttgct cttcgagatg tcatcagcaa gttccaggaa gt#tcctttgg   1320gacctttacc tcccccgagc cccaagatga tgcttggacc tgtgactctg ca#cctggttg   1380ggcatttact ggctttccta gacttgcttt gcccccgtgg gcccattcat tc#aatcttgc   1440caatgacctt tgaggctgtc aagcaggacc atggcttcat gttgtaccga ac#ctatatga   1500cccataccat ttttgagcca acaccattct gggtgccaaa taatggagtc ca#tgaccgtg   1560cctatgtgat ggtggatggg gtgttccagg gtgttgtgga gcgaaatatg ag#agacaaac   1620tatttttgac ggggaaactg gggtccaaac tggatatctt ggtggagaac at#ggggaggc   1680tcagctttgg gtctaacagc agtgacttca agggcctgtt gaagccacca at#tctggggc   1740aaacaatcct tacccagtgg atgatgttcc ctctgaaaat tgataacctt gt#gaagtggt   1800ggtttcccct ccagttgcca aaatggccat atcctcaagc tccttctggc cc#cacattct   1860actccaaaac atttccaatt ttaggctcag ttggggacac atttctatat ct#acctggat   1920ggaccaaggg ccaagtctgg atcaatgggt ttaacttggg ccggtactgg ac#aaagcagg   1980ggccacaaca gaccctctac gtgccaagat tcctgctgtt tcctagggga gc#cctcaaca   2040aaattacatt gctggaacta gaagatgtac ctctccagcc ccaagtccaa tt#tttggata   2100agcctatcct caatagcact agtactttgc acaggacaca tatcaattcc ct#ttcagctg   2160atacactgag tgcctctgaa ccaatggagt taagtgggca ctgaaaggta gg#ccgggcat   2220ggtggctcat gcctgtaatc ccagcacttt gggaggctga gacgggtgga tt#acctgagg   2280tcaggacttc aagaccagcc tggccaacat ggtgaaaccc cgtctccact aa#aaatacaa   2340aaattagccg ggcgtgatgg tgggcacctc taatcccagc tacttgggag gc#tgagggca   2400ggagaattgc ttgaatccag gaggcagagg ttgcagtgag tggaggttgt ac#cactgcac   2460 tccagcctgg ctgacagtga gacactccat ctcaaaaaaa aaaaa   #                2505 <210> SEQ ID NO 177 <211> LENGTH: 654<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 177Met Ala Pro Lys Lys Leu Ser Cys Leu Arg Se #r Leu Leu Leu Pro Leu  1               5  #                 10  #                 15Ser Leu Thr Leu Leu Leu Pro Gln Ala Asp Th #r Arg Ser Phe Val Val             20      #             25      #             30Asp Arg Gly His Asp Arg Phe Leu Leu Asp Gl #y Ala Pro Phe Arg Tyr         35          #         40          #         45Val Ser Gly Ser Leu His Tyr Phe Arg Val Pr #o Arg Val Leu Trp Ala     50              #     55              #     60Asp Arg Leu Leu Lys Met Arg Trp Ser Gly Le #u Asn Ala Ile Gln Phe 65                  # 70                  # 75                  # 80Tyr Val Pro Trp Asn Tyr His Glu Pro Gln Pr #o Gly Val Tyr Asn Phe                 85  #                 90  #                 95Asn Gly Ser Arg Asp Leu Ile Ala Phe Leu As #n Glu Ala Ala Leu Ala            100       #           105       #           110Asn Leu Leu Val Ile Leu Arg Pro Gly Pro Ty #r Ile Cys Ala Glu Trp        115           #       120           #       125Glu Met Gly Gly Leu Pro Ser Trp Leu Leu Ar #g Lys Pro Glu Ile His    130               #   135               #   140Leu Arg Thr Ser Asp Pro Asp Phe Leu Ala Al #a Val Asp Ser Trp Phe145                 1 #50                 1 #55                 1 #60Lys Val Leu Leu Pro Lys Ile Tyr Pro Trp Le #u Tyr His Asn Gly Gly                165   #               170   #               175Asn Ile Ile Ser Ile Gln Val Glu Asn Glu Ty #r Gly Ser Tyr Arg Ala            180       #           185       #           190Cys Asp Phe Ser Tyr Met Arg His Leu Ala Gl #y Leu Phe Arg Ala Leu        195           #       200           #       205Leu Gly Glu Lys Ile Leu Leu Phe Thr Thr As #p Gly Pro Glu Gly Leu    210               #   215               #   220Lys Cys Gly Ser Leu Arg Gly Leu Tyr Thr Th #r Val Asp Phe Gly Pro225                 2 #30                 2 #35                 2 #40Ala Asp Asn Met Thr Lys Ile Phe Thr Leu Le #u Arg Lys Tyr Glu Pro                245   #               250   #               255His Gly Pro Leu Val Asn Ser Glu Tyr Tyr Th #r Gly Trp Leu Asp Tyr            260       #           265       #           270Trp Gly Gln Asn His Ser Thr Arg Ser Val Se #r Ala Val Thr Lys Gly        275           #       280           #       285Leu Glu Asn Met Leu Lys Leu Gly Ala Ser Va #l Asn Met Tyr Met Phe    290               #   295               #   300His Gly Gly Thr Asn Phe Gly Tyr Trp Asn Gl #y Ala Asp Lys Lys Gly305                 3 #10                 3 #15                 3 #20Arg Phe Leu Pro Ile Thr Thr Ser Tyr Asp Ty #r Asp Ala Pro Ile Ser                325   #               330   #               335Glu Ala Gly Asp Pro Thr Pro Lys Leu Phe Al #a Leu Arg Asp Val Ile            340       #           345       #           350Ser Lys Phe Gln Glu Val Pro Leu Gly Pro Le #u Pro Pro Pro Ser Pro        355           #       360           #       365Lys Met Met Leu Gly Pro Val Thr Leu His Le #u Val Gly His Leu Leu    370               #   375               #   380Ala Phe Leu Asp Leu Leu Cys Pro Arg Gly Pr #o Ile His Ser Ile Leu385                 3 #90                 3 #95                 4 #00Pro Met Thr Phe Glu Ala Val Lys Gln Asp Hi #s Gly Phe Met Leu Tyr                405   #               410   #               415Arg Thr Tyr Met Thr His Thr Ile Phe Glu Pr #o Thr Pro Phe Trp Val            420       #           425       #           430Pro Asn Asn Gly Val His Asp Arg Ala Tyr Va #l Met Val Asp Gly Val        435           #       440           #       445Phe Gln Gly Val Val Glu Arg Asn Met Arg As #p Lys Leu Phe Leu Thr    450               #   455               #   460Gly Lys Leu Gly Ser Lys Leu Asp Ile Leu Va #l Glu Asn Met Gly Arg465                 4 #70                 4 #75                 4 #80Leu Ser Phe Gly Ser Asn Ser Ser Asp Phe Ly #s Gly Leu Leu Lys Pro                485   #               490   #               495Pro Ile Leu Gly Gln Thr Ile Leu Thr Gln Tr #p Met Met Phe Pro Leu            500       #           505       #           510Lys Ile Asp Asn Leu Val Lys Trp Trp Phe Pr #o Leu Gln Leu Pro Lys        515           #       520           #       525Trp Pro Tyr Pro Gln Ala Pro Ser Gly Pro Th #r Phe Tyr Ser Lys Thr    530               #   535               #   540Phe Pro Ile Leu Gly Ser Val Gly Asp Thr Ph #e Leu Tyr Leu Pro Gly545                 5 #50                 5 #55                 5 #60Trp Thr Lys Gly Gln Val Trp Ile Asn Gly Ph #e Asn Leu Gly Arg Tyr                565   #               570   #               575Trp Thr Lys Gln Gly Pro Gln Gln Thr Leu Ty #r Val Pro Arg Phe Leu            580       #           585       #           590Leu Phe Pro Arg Gly Ala Leu Asn Lys Ile Th #r Leu Leu Glu Leu Glu        595           #       600           #       605Asp Val Pro Leu Gln Pro Gln Val Gln Phe Le #u Asp Lys Pro Ile Leu    610               #   615               #   620Asn Ser Thr Ser Thr Leu His Arg Thr His Il #e Asn Ser Leu Ser Ala625                 6 #30                 6 #35                 6 #40Asp Thr Leu Ser Ala Ser Glu Pro Met Glu Le #u Ser Gly His                645   #               650 <210> SEQ ID NO 178<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 178tggctactcc aagaccctgg catg           #                  #                24 <210> SEQ ID NO 179 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 179tggacaaatc cccttgctca gccc           #                  #                24 <210> SEQ ID NO 180 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 180gggcttcacc gaagcagtgg acctttattt tgaccacctg atgtccaggg  #              50 <210> SEQ ID NO 181 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 181ccagctatga ctatgatgca cc            #                  #                 22 <210> SEQ ID NO 182 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 182tggcacccag aatggtgttg gctc           #                  #                24 <210> SEQ ID NO 183 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 183cgagatgtca tcagcaagtt ccaggaagtt cctttgggac ctttacctcc  #              50 <210> SEQ ID NO 184 <211> LENGTH: 1947 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 184gctttgaaca cgtctgcaag cccaaagttg agcatctgat tggttatgag gt#atttgagt     60gcacccacaa tatggcttac atgttgaaaa agcttctcat cagttacata tc#cattattt    120gtgtttatgg ctttatctgc ctctacactc tcttctggtt attcaggata cc#tttgaagg    180aatattcttt cgaaaaagtc agagaagaga gcagttttag tgacattcca ga#tgtcaaaa    240acgattttgc gttccttctt cacatggtag accagtatga ccagctatat tc#caagcgtt    300ttggtgtgtt cttgtcagaa gttagtgaaa ataaacttag ggaaattagt tt#gaaccatg    360agtggacatt tgaaaaactc aggcagcaca tttcacgcaa cgcccaggac aa#gcaggagt    420tgcatctgtt catgctgtcg ggggtgcccg atgctgtctt tgacctcaca ga#cctggatg    480tgctaaagct tgaactaatt ccagaagcta aaattcctgc taagatttct ca#aatgacta    540acctccaaga gctccacctc tgccactgcc ctgcaaaagt tgaacagact gc#ttttagct    600ttcttcgcga tcacttgaga tgccttcacg tgaagttcac tgatgtggct ga#aattcctg    660cctgggtgta tttgctcaaa aaccttcgag agttgtactt aataggcaat tt#gaactctg    720aaaacaataa gatgatagga cttgaatctc tccgagagtt gcggcacctt aa#gattctcc    780acgtgaagag caatttgacc aaagttccct ccaacattac agatgtggct cc#acatctta    840caaagttagt cattcataat gacggcacta aactcttggt actgaacagc ct#taagaaaa    900tgatgaatgt cgctgagctg gaactccaga actgtgagct agagagaatc cc#acatgcta    960ttttcagcct ctctaattta caggaactgg atttaaagtc caataacatt cg#cacaattg   1020aggaaatcat cagtttccag catttaaaac gactgacttg tttaaaatta tg#gcataaca   1080aaattgttac tattcctccc tctattaccc atgtcaaaaa cttggagtca ct#ttatttct   1140ctaacaacaa gctcgaatcc ttaccagtgg cagtatttag tttacagaaa ct#cagatgct   1200tagatgtgag ctacaacaac atttcaatga ttccaataga aataggattg ct#tcagaacc   1260tgcagcattt gcatatcact gggaacaaag tggacattct gccaaaacaa tt#gtttaaat   1320gcataaagtt gaggactttg aatctgggac agaactgcat cacctcactc cc#agagaaag   1380ttggtcagct ctcccagctc actcagctgg agctgaaggg gaactgcttg ga#ccgcctgc   1440cagcccagct gggccagtgt cggatgctca agaaaagcgg gcttgttgtg ga#agatcacc   1500tttttgatac cctgccactc gaagtcaaag aggcattgaa tcaagacata aa#tattccct   1560ttgcaaatgg gatttaaact aagataatat atgcacagtg atgtgcagga ac#aacttcct   1620agattgcaag tgctcacgta caagttatta caagataatg cattttagga gt#agatacat   1680cttttaaaat aaaacagaga ggatgcatag aaggctgata gaagacataa ct#gaatgttc   1740aatgtttgta gggttttaag tcattcattt ccaaatcatt tttttttttc tt#ttggggaa   1800agggaaggaa aaattataat cactaatctt ggttcttttt aaattgtttg ta#acttggat   1860gctgccgcta ctgaatgttt acaaattgct tgcctgctaa agtaaatgat ta#aattgaca   1920 ttttcttact aaaaaaaaaa aaaaaaa          #                   #           1947 <210> SEQ ID NO 185<211> LENGTH: 501 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 185 Met Ala Tyr Met Leu Lys Lys Leu Leu Ile Se#r Tyr Ile Ser Ile Ile   1               5  #                 10 #                 15 Cys Val Tyr Gly Phe Ile Cys Leu Tyr Thr Le#u Phe Trp Leu Phe Arg              20      #             25     #             30 Ile Pro Leu Lys Glu Tyr Ser Phe Glu Lys Va#l Arg Glu Glu Ser Ser          35          #         40         #         45 Phe Ser Asp Ile Pro Asp Val Lys Asn Asp Ph#e Ala Phe Leu Leu His      50              #     55             #     60 Met Val Asp Gln Tyr Asp Gln Leu Tyr Ser Ly#s Arg Phe Gly Val Phe  65                  # 70                 # 75                  # 80 Leu Ser Glu Val Ser Glu Asn Lys Leu Arg Gl#u Ile Ser Leu Asn His                  85  #                 90 #                 95 Glu Trp Thr Phe Glu Lys Leu Arg Gln His Il#e Ser Arg Asn Ala Gln             100       #           105      #           110 Asp Lys Gln Glu Leu His Leu Phe Met Leu Se#r Gly Val Pro Asp Ala         115           #       120          #       125 Val Phe Asp Leu Thr Asp Leu Asp Val Leu Ly#s Leu Glu Leu Ile Pro     130               #   135              #   140 Glu Ala Lys Ile Pro Ala Lys Ile Ser Gln Me#t Thr Asn Leu Gln Glu 145                 1 #50                 1#55                 1 #60 Leu His Leu Cys His Cys Pro Ala Lys Val Gl#u Gln Thr Ala Phe Ser                 165   #               170  #               175 Phe Leu Arg Asp His Leu Arg Cys Leu His Va#l Lys Phe Thr Asp Val             180       #           185      #           190 Ala Glu Ile Pro Ala Trp Val Tyr Leu Leu Ly#s Asn Leu Arg Glu Leu         195           #       200          #       205 Tyr Leu Ile Gly Asn Leu Asn Ser Glu Asn As#n Lys Met Ile Gly Leu     210               #   215              #   220 Glu Ser Leu Arg Glu Leu Arg His Leu Lys Il#e Leu His Val Lys Ser 225                 2 #30                 2#35                 2 #40 Asn Leu Thr Lys Val Pro Ser Asn Ile Thr As#p Val Ala Pro His Leu                 245   #               250  #               255 Thr Lys Leu Val Ile His Asn Asp Gly Thr Ly#s Leu Leu Val Leu Asn             260       #           265      #           270 Ser Leu Lys Lys Met Met Asn Val Ala Glu Le#u Glu Leu Gln Asn Cys         275           #       280          #       285 Glu Leu Glu Arg Ile Pro His Ala Ile Phe Se#r Leu Ser Asn Leu Gln     290               #   295              #   300 Glu Leu Asp Leu Lys Ser Asn Asn Ile Arg Th#r Ile Glu Glu Ile Ile 305                 3 #10                 3#15                 3 #20 Ser Phe Gln His Leu Lys Arg Leu Thr Cys Le#u Lys Leu Trp His Asn                 325   #               330  #               335 Lys Ile Val Thr Ile Pro Pro Ser Ile Thr Hi#s Val Lys Asn Leu Glu             340       #           345      #           350 Ser Leu Tyr Phe Ser Asn Asn Lys Leu Glu Se#r Leu Pro Val Ala Val         355           #       360          #       365 Phe Ser Leu Gln Lys Leu Arg Cys Leu Asp Va#l Ser Tyr Asn Asn Ile     370               #   375              #   380 Ser Met Ile Pro Ile Glu Ile Gly Leu Leu Gl#n Asn Leu Gln His Leu 385                 3 #90                 3#95                 4 #00 His Ile Thr Gly Asn Lys Val Asp Ile Leu Pr#o Lys Gln Leu Phe Lys                 405   #               410  #               415 Cys Ile Lys Leu Arg Thr Leu Asn Leu Gly Gl#n Asn Cys Ile Thr Ser             420       #           425      #           430 Leu Pro Glu Lys Val Gly Gln Leu Ser Gln Le#u Thr Gln Leu Glu Leu         435           #       440          #       445 Lys Gly Asn Cys Leu Asp Arg Leu Pro Ala Gl#n Leu Gly Gln Cys Arg     450               #   455              #   460 Met Leu Lys Lys Ser Gly Leu Val Val Glu As#p His Leu Phe Asp Thr 465                 4 #70                 4#75                 4 #80 Leu Pro Leu Glu Val Lys Glu Ala Leu Asn Gl#n Asp Ile Asn Ile Pro                 485   #               490  #               495 Phe Ala Asn Gly Ile             500<210> SEQ ID NO 186 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 186cctccctcta ttacccatgt c            #                  #                   #21 <210> SEQ ID NO 187 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 187gaccaacttt ctctgggagt gagg           #                  #                24 <210> SEQ ID NO 188 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 188gtcactttat ttctctaaca acaagctcga atccttacca gtggcag   #                47 <210> SEQ ID NO 189 <211> LENGTH: 2917<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 189cccacgcgtc cggccttctc tctggacttt gcatttccat tccttttcat tg#acaaactg     60acttttttta tttctttttt tccatctctg ggccagcttg ggatcctagg cc#gccctggg    120aagacatttg tgttttacac acataaggat ctgtgtttgg ggtttcttct tc#ctcccctg    180acattggcat tgcttagtgg ttgtgtgggg agggagacca cgtgggctca gt#gcttgctt    240gcacttatct gcctaggtac atcgaagtct tttgacctcc atacagtgat ta#tgcctgtc    300atcgctggtg gtatcctggc ggccttgctc ctgctgatag ttgtcgtgct ct#gtctttac    360ttcaaaatac acaacgcgct aaaagctgca aaggaacctg aagctgtggc tg#taaaaaat    420cacaacccag acaaggtgtg gtgggccaag aacagccagg ccaaaaccat tg#ccacggag    480tcttgtcctg ccctgcagtg ctgtgaagga tatagaatgt gtgccagttt tg#attccctg    540ccaccttgct gttgcgacat aaatgagggc ctctgagtta ggaaaggctc cc#ttctcaaa    600gcagagccct gaagacttca atgatgtcaa tgaggccacc tgtttgtgat gt#gcaggcac    660agaagaaagg cacagctccc catcagtttc atggaaaata actcagtgcc tg#ctgggaac    720cagctgctgg agatccctac agagagcttc cactgggggc aacccttcca gg#aaggagtt    780ggggagagag aaccctcact gtggggaatg ctgataaacc agtcacacag ct#gctctatt    840ctcacacaaa tctacccctt gcgtggctgg aactgacgtt tccctggagg tg#tccagaaa    900gctgatgtaa cacagagcct ataaaagctg tcggtcctta aggctgccca gc#gccttgcc    960aaaatggagc ttgtaagaag gctcatgcca ttgaccctct taattctctc ct#gtttggcg   1020gagctgacaa tggcggaggc tgaaggcaat gcaagctgca cagtcagtct ag#ggggtgcc   1080aatatggcag agacccacaa agccatgatc ctgcaactca atcccagtga ga#actgcacc   1140tggacaatag aaagaccaga aaacaaaagc atcagaatta tcttttccta tg#tccagctt   1200gatccagatg gaagctgtga aagtgaaaac attaaagtct ttgacggaac ct#ccagcaat   1260gggcctctgc tagggcaagt ctgcagtaaa aacgactatg ttcctgtatt tg#aatcatca   1320tccagtacat tgacgtttca aatagttact gactcagcaa gaattcaaag aa#ctgtcttt   1380gtcttctact acttcttctc tcctaacatc tctattccaa actgtggcgg tt#acctggat   1440accttggaag gatccttcac cagccccaat tacccaaagc cgcatcctga gc#tggcttat   1500tgtgtgtggc acatacaagt ggagaaagat tacaagataa aactaaactt ca#aagagatt   1560ttcctagaaa tagacaaaca gtgcaaattt gattttcttg ccatctatga tg#gcccctcc   1620accaactctg gcctgattgg acaagtctgt ggccgtgtga ctcccacctt cg#aatcgtca   1680tcaaactctc tgactgtcgt gttgtctaca gattatgcca attcttaccg gg#gattttct   1740gcttcctaca cctcaattta tgcagaaaac atcaacacta catctttaac tt#gctcttct   1800gacaggatga gagttattat aagcaaatcc tacctagagg cttttaactc ta#atgggaat   1860aacttgcaac taaaagaccc aacttgcaga ccaaaattat caaatgttgt gg#aattttct   1920gtccctctta atggatgtgg tacaatcaga aaggtagaag atcagtcaat ta#cttacacc   1980aatataatca ccttttctgc atcctcaact tctgaagtga tcacccgtca ga#aacaactc   2040cagattattg tgaagtgtga aatgggacat aattctacag tggagataat at#acataaca   2100gaagatgatg taatacaaag tcaaaatgca ctgggcaaat ataacaccag ca#tggctctt   2160tttgaatcca attcatttga aaagactata cttgaatcac catattatgt gg#atttgaac   2220caaactcttt ttgttcaagt tagtctgcac acctcagatc caaatttggt gg#tgtttctt   2280gatacctgta gagcctctcc cacctctgac tttgcatctc caacctacga cc#taatcaag   2340agtggatgta gtcgagatga aacttgtaag gtgtatccct tatttggaca ct#atgggaga   2400ttccagttta atgcctttaa attcttgaga agtatgagct ctgtgtatct gc#agtgtaaa   2460gttttgatat gtgatagcag tgaccaccag tctcgctgca atcaaggttg tg#tctccaga   2520agcaaacgag acatttcttc atataaatgg aaaacagatt ccatcatagg ac#ccattcgt   2580ctgaaaaggg atcgaagtgc aagtggcaat tcaggatttc agcatgaaac ac#atgcggaa   2640gaaactccaa accagccttt caacagtgtg catctgtttt ccttcatggt tc#tagctctg   2700aatgtggtga ctgtagcgac aatcacagtg aggcattttg taaatcaacg gg#cagactac   2760aaataccaga agctgcagaa ctattaacta acaggtccaa ccctaagtga ga#catgtttc   2820tccaggatgc caaaggaaat gctacctcgt ggctacacat attatgaata aa#tgaggaag   2880 ggcctgaaag tgacacacag gcctgcatgt aaaaaaa      #                   #    2917 <210> SEQ ID NO 190 <211> LENGTH: 607<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 190Met Glu Leu Val Arg Arg Leu Met Pro Leu Th #r Leu Leu Ile Leu Ser  1               5  #                 10  #                 15Cys Leu Ala Glu Leu Thr Met Ala Glu Ala Gl #u Gly Asn Ala Ser Cys             20      #             25      #             30Thr Val Ser Leu Gly Gly Ala Asn Met Ala Gl #u Thr His Lys Ala Met         35          #         40          #         45Ile Leu Gln Leu Asn Pro Ser Glu Asn Cys Th #r Trp Thr Ile Glu Arg     50              #     55              #     60Pro Glu Asn Lys Ser Ile Arg Ile Ile Phe Se #r Tyr Val Gln Leu Asp 65                  # 70                  # 75                  # 80Pro Asp Gly Ser Cys Glu Ser Glu Asn Ile Ly #s Val Phe Asp Gly Thr                 85  #                 90  #                 95Ser Ser Asn Gly Pro Leu Leu Gly Gln Val Cy #s Ser Lys Asn Asp Tyr            100       #           105       #           110Val Pro Val Phe Glu Ser Ser Ser Ser Thr Le #u Thr Phe Gln Ile Val        115           #       120           #       125Thr Asp Ser Ala Arg Ile Gln Arg Thr Val Ph #e Val Phe Tyr Tyr Phe    130               #   135               #   140Phe Ser Pro Asn Ile Ser Ile Pro Asn Cys Gl #y Gly Tyr Leu Asp Thr145                 1 #50                 1 #55                 1 #60Leu Glu Gly Ser Phe Thr Ser Pro Asn Tyr Pr #o Lys Pro His Pro Glu                165   #               170   #               175Leu Ala Tyr Cys Val Trp His Ile Gln Val Gl #u Lys Asp Tyr Lys Ile            180       #           185       #           190Lys Leu Asn Phe Lys Glu Ile Phe Leu Glu Il #e Asp Lys Gln Cys Lys        195           #       200           #       205Phe Asp Phe Leu Ala Ile Tyr Asp Gly Pro Se #r Thr Asn Ser Gly Leu    210               #   215               #   220Ile Gly Gln Val Cys Gly Arg Val Thr Pro Th #r Phe Glu Ser Ser Ser225                 2 #30                 2 #35                 2 #40Asn Ser Leu Thr Val Val Leu Ser Thr Asp Ty #r Ala Asn Ser Tyr Arg                245   #               250   #               255Gly Phe Ser Ala Ser Tyr Thr Ser Ile Tyr Al #a Glu Asn Ile Asn Thr            260       #           265       #           270Thr Ser Leu Thr Cys Ser Ser Asp Arg Met Ar #g Val Ile Ile Ser Lys        275           #       280           #       285Ser Tyr Leu Glu Ala Phe Asn Ser Asn Gly As #n Asn Leu Gln Leu Lys    290               #   295               #   300Asp Pro Thr Cys Arg Pro Lys Leu Ser Asn Va #l Val Glu Phe Ser Val305                 3 #10                 3 #15                 3 #20Pro Leu Asn Gly Cys Gly Thr Ile Arg Lys Va #l Glu Asp Gln Ser Ile                325   #               330   #               335Thr Tyr Thr Asn Ile Ile Thr Phe Ser Ala Se #r Ser Thr Ser Glu Val            340       #           345       #           350Ile Thr Arg Gln Lys Gln Leu Gln Ile Ile Va #l Lys Cys Glu Met Gly        355           #       360           #       365His Asn Ser Thr Val Glu Ile Ile Tyr Ile Th #r Glu Asp Asp Val Ile    370               #   375               #   380Gln Ser Gln Asn Ala Leu Gly Lys Tyr Asn Th #r Ser Met Ala Leu Phe385                 3 #90                 3 #95                 4 #00Glu Ser Asn Ser Phe Glu Lys Thr Ile Leu Gl #u Ser Pro Tyr Tyr Val                405   #               410   #               415Asp Leu Asn Gln Thr Leu Phe Val Gln Val Se #r Leu His Thr Ser Asp            420       #           425       #           430Pro Asn Leu Val Val Phe Leu Asp Thr Cys Ar #g Ala Ser Pro Thr Ser        435           #       440           #       445Asp Phe Ala Ser Pro Thr Tyr Asp Leu Ile Ly #s Ser Gly Cys Ser Arg    450               #   455               #   460Asp Glu Thr Cys Lys Val Tyr Pro Leu Phe Gl #y His Tyr Gly Arg Phe465                 4 #70                 4 #75                 4 #80Gln Phe Asn Ala Phe Lys Phe Leu Arg Ser Me #t Ser Ser Val Tyr Leu                485   #               490   #               495Gln Cys Lys Val Leu Ile Cys Asp Ser Ser As #p His Gln Ser Arg Cys            500       #           505       #           510Asn Gln Gly Cys Val Ser Arg Ser Lys Arg As #p Ile Ser Ser Tyr Lys        515           #       520           #       525Trp Lys Thr Asp Ser Ile Ile Gly Pro Ile Ar #g Leu Lys Arg Asp Arg    530               #   535               #   540Ser Ala Ser Gly Asn Ser Gly Phe Gln His Gl #u Thr His Ala Glu Glu545                 5 #50                 5 #55                 5 #60Thr Pro Asn Gln Pro Phe Asn Ser Val His Le #u Phe Ser Phe Met Val                565   #               570   #               575Leu Ala Leu Asn Val Val Thr Val Ala Thr Il #e Thr Val Arg His Phe            580       #           585       #           590Val Asn Gln Arg Ala Asp Tyr Lys Tyr Gln Ly #s Leu Gln Asn Tyr        595           #       600           #       605<210> SEQ ID NO 191 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 191tctctattcc aaactgtggc g            #                  #                   #21 <210> SEQ ID NO 192 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 192tttgatgacg attcgaaggt gg            #                  #                 22 <210> SEQ ID NO 193 <211> LENGTH: 47<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 193ggaaggatcc ttcaccagcc ccaattaccc aaagccgcat cctgagc   #                47 <210> SEQ ID NO 194 <211> LENGTH: 2362<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 194gacggaagaa cagcgctccc gaggccgcgg gagcctgcag agaggacagc cg#gcctgcgc     60cgggacatgc ggccccagga gctccccagg ctcgcgttcc cgttgctgct gt#tgctgttg    120ctgctgctgc cgccgccgcc gtgccctgcc cacagcgcca cgcgcttcga cc#ccacctgg    180gagtccctgg acgcccgcca gctgcccgcg tggtttgacc aggccaagtt cg#gcatcttc    240atccactggg gagtgttttc cgtgcccagc ttcggtagcg agtggttctg gt#ggtattgg    300caaaaggaaa agataccgaa gtatgtggaa tttatgaaag ataattaccc tc#ctagtttc    360aaatatgaag attttggacc actatttaca gcaaaatttt ttaatgccaa cc#agtgggca    420gatatttttc aggcctctgg tgccaaatac attgtcttaa cttccaaaca tc#atgaaggc    480tttaccttgt gggggtcaga atattcgtgg aactggaatg ccatagatga gg#ggcccaag    540agggacattg tcaaggaact tgaggtagcc attaggaaca gaactgacct gc#gttttgga    600ctgtactatt ccctttttga atggtttcat ccgctcttcc ttgaggatga at#ccagttca    660ttccataagc ggcaatttcc agtttctaag acattgccag agctctatga gt#tagtgaac    720aactatcagc ctgaggttct gtggtcggat ggtgacggag gagcaccgga tc#aatactgg    780aacagcacag gcttcttggc ctggttatat aatgaaagcc cagttcgggg ca#cagtagtc    840accaatgatc gttggggagc tggtagcatc tgtaagcatg gtggcttcta ta#cctgcagt    900gatcgttata acccaggaca tcttttgcca cataaatggg aaaactgcat ga#caatagac    960aaactgtcct ggggctatag gagggaagct ggaatctctg actatcttac aa#ttgaagaa   1020ttggtgaagc aacttgtaga gacagtttca tgtggaggaa atcttttgat ga#atattggg   1080cccacactag atggcaccat ttctgtagtt tttgaggagc gactgaggca ag#tggggtcc   1140tggctaaaag tcaatggaga agctatttat gaaacctata cctggcgatc cc#agaatgac   1200actgtcaccc cagatgtgtg gtacacatcc aagcctaaag aaaaattagt ct#atgccatt   1260tttcttaaat ggcccacatc aggacagctg ttccttggcc atcccaaagc ta#ttctgggg   1320gcaacagagg tgaaactact gggccatgga cagccactta actggatttc tt#tggagcaa   1380aatggcatta tggtagaact gccacagcta accattcatc agatgccgtg ta#aatggggc   1440tgggctctag ccctaactaa tgtgatctaa agtgcagcag agtggctgat gc#tgcaagtt   1500atgtctaagg ctaggaacta tcaggtgtct ataattgtag cacatggaga aa#gcaatgta   1560aactggataa gaaaattatt tggcagttca gccctttccc tttttcccac ta#aatttttc   1620ttaaattacc catgtaacca ttttaactct ccagtgcact ttgccattaa ag#tctcttca   1680cattgatttg tttccatgtg tgactcagag gtgagaattt tttcacatta ta#gtagcaag   1740gaattggtgg tattatggac cgaactgaaa attttatgtt gaagccatat cc#cccatgat   1800tatatagtta tgcatcactt aatatgggga tattttctgg gaaatgcatt gc#tagtcaat   1860ttttttttgt gccaacatca tagagtgtat ttacaaaatc ctagatggca ta#gcctacta   1920cacacctaat gtgtatggta tagactgttg ctcctaggct acagacatat ac#agcatgtt   1980actgaatact gtaggcaata gtaacagtgg tatttgtata tcgaaacata tg#gaaacata   2040gagaaggtac agtaaaaata ctgtaaaata aatggtgcac ctgtataggg ca#cttaccac   2100gaatggagct tacaggactg gaagttgctc tgggtgagtc agtgagtgaa tg#tgaaggcc   2160taggacatta ttgaacactg ccagacgtta taaatactgt atgcttaggc ta#cactacat   2220ttataaaaaa aagtttttct ttcttcaatt ataaattaac ataagtgtac tg#taacttta   2280caaacgtttt aatttttaaa acctttttgg ctcttttgta ataacactta gc#ttaaaaca   2340 taaactcatt gtgcaaatgt aa            #                  #               2362 <210> SEQ ID NO 195 <211> LENGTH: 467<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 195Met Arg Pro Gln Glu Leu Pro Arg Leu Ala Ph #e Pro Leu Leu Leu Leu  1               5  #                 10  #                 15Leu Leu Leu Leu Leu Pro Pro Pro Pro Cys Pr #o Ala His Ser Ala Thr             20      #             25      #             30Arg Phe Asp Pro Thr Trp Glu Ser Leu Asp Al #a Arg Gln Leu Pro Ala         35          #         40          #         45Trp Phe Asp Gln Ala Lys Phe Gly Ile Phe Il #e His Trp Gly Val Phe     50              #     55              #     60Ser Val Pro Ser Phe Gly Ser Glu Trp Phe Tr #p Trp Tyr Trp Gln Lys 65                  # 70                  # 75                  # 80Glu Lys Ile Pro Lys Tyr Val Glu Phe Met Ly #s Asp Asn Tyr Pro Pro                 85  #                 90  #                 95Ser Phe Lys Tyr Glu Asp Phe Gly Pro Leu Ph #e Thr Ala Lys Phe Phe            100       #           105       #           110Asn Ala Asn Gln Trp Ala Asp Ile Phe Gln Al #a Ser Gly Ala Lys Tyr        115           #       120           #       125Ile Val Leu Thr Ser Lys His His Glu Gly Ph #e Thr Leu Trp Gly Ser    130               #   135               #   140Glu Tyr Ser Trp Asn Trp Asn Ala Ile Asp Gl #u Gly Pro Lys Arg Asp145                 1 #50                 1 #55                 1 #60Ile Val Lys Glu Leu Glu Val Ala Ile Arg As #n Arg Thr Asp Leu Arg                165   #               170   #               175Phe Gly Leu Tyr Tyr Ser Leu Phe Glu Trp Ph #e His Pro Leu Phe Leu            180       #           185       #           190Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gl #n Phe Pro Val Ser Lys        195           #       200           #       205Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn As #n Tyr Gln Pro Glu Val    210               #   215               #   220Leu Trp Ser Asp Gly Asp Gly Gly Ala Pro As #p Gln Tyr Trp Asn Ser225                 2 #30                 2 #35                 2 #40Thr Gly Phe Leu Ala Trp Leu Tyr Asn Glu Se #r Pro Val Arg Gly Thr                245   #               250   #               255Val Val Thr Asn Asp Arg Trp Gly Ala Gly Se #r Ile Cys Lys His Gly            260       #           265       #           270Gly Phe Tyr Thr Cys Ser Asp Arg Tyr Asn Pr #o Gly His Leu Leu Pro        275           #       280           #       285His Lys Trp Glu Asn Cys Met Thr Ile Asp Ly #s Leu Ser Trp Gly Tyr    290               #   295               #   300Arg Arg Glu Ala Gly Ile Ser Asp Tyr Leu Th #r Ile Glu Glu Leu Val305                 3 #10                 3 #15                 3 #20Lys Gln Leu Val Glu Thr Val Ser Cys Gly Gl #y Asn Leu Leu Met Asn                325   #               330   #               335Ile Gly Pro Thr Leu Asp Gly Thr Ile Ser Va #l Val Phe Glu Glu Arg            340       #           345       #           350Leu Arg Gln Val Gly Ser Trp Leu Lys Val As #n Gly Glu Ala Ile Tyr        355           #       360           #       365Glu Thr Tyr Thr Trp Arg Ser Gln Asn Asp Th #r Val Thr Pro Asp Val    370               #   375               #   380Trp Tyr Thr Ser Lys Pro Lys Glu Lys Leu Va #l Tyr Ala Ile Phe Leu385                 3 #90                 3 #95                 4 #00Lys Trp Pro Thr Ser Gly Gln Leu Phe Leu Gl #y His Pro Lys Ala Ile                405   #               410   #               415Leu Gly Ala Thr Glu Val Lys Leu Leu Gly Hi #s Gly Gln Pro Leu Asn            420       #           425       #           430Trp Ile Ser Leu Glu Gln Asn Gly Ile Met Va #l Glu Leu Pro Gln Leu        435           #       440           #       445Thr Ile His Gln Met Pro Cys Lys Trp Gly Tr #p Ala Leu Ala Leu Thr    450               #   455               #   460 Asn Val Ile 465<210> SEQ ID NO 196 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 196tggtttgacc aggccaagtt cgg            #                  #                23 <210> SEQ ID NO 197 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 197ggattcatcc tcaaggaaga gcgg           #                  #                24 <210> SEQ ID NO 198 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 198aacttgcagc atcagccact ctgc           #                  #                24 <210> SEQ ID NO 199 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 199ttccgtgccc agcttcggta gcgagtggtt ctggtggtat tggca    #                  #45 <210> SEQ ID NO 200 <211> LENGTH: 2372 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 200agcagggaaa tccggatgtc tcggttatga agtggagcag tgagtgtgag cc#tcaacata     60gttccagaac tctccatccg gactagttat tgagcatctg cctctcatat ca#ccagtggc    120catctgaggt gtttccctgg ctctgaaggg gtaggcacga tggccaggtg ct#tcagcctg    180gtgttgcttc tcacttccat ctggaccacg aggctcctgg tccaaggctc tt#tgcgtgca    240gaagagcttt ccatccaggt gtcatgcaga attatgggga tcacccttgt ga#gcaaaaag    300gcgaaccagc agctgaattt cacagaagct aaggaggcct gtaggctgct gg#gactaagt    360ttggccggca aggaccaagt tgaaacagcc ttgaaagcta gctttgaaac tt#gcagctat    420ggctgggttg gagatggatt cgtggtcatc tctaggatta gcccaaaccc ca#agtgtggg    480aaaaatgggg tgggtgtcct gatttggaag gttccagtga gccgacagtt tg#cagcctat    540tgttacaact catctgatac ttggactaac tcgtgcattc cagaaattat ca#ccaccaaa    600gatcccatat tcaacactca aactgcaaca caaacaacag aatttattgt ca#gtgacagt    660acctactcgg tggcatcccc ttactctaca atacctgccc ctactactac tc#ctcctgct    720ccagcttcca cttctattcc acggagaaaa aaattgattt gtgtcacaga ag#tttttatg    780gaaactagca ccatgtctac agaaactgaa ccatttgttg aaaataaagc ag#cattcaag    840aatgaagctg ctgggtttgg aggtgtcccc acggctctgc tagtgcttgc tc#tcctcttc    900tttggtgctg cagctggtct tggattttgc tatgtcaaaa ggtatgtgaa gg#ccttccct    960tttacaaaca agaatcagca gaaggaaatg atcgaaacca aagtagtaaa gg#aggagaag   1020gccaatgata gcaaccctaa tgaggaatca aagaaaactg ataaaaaccc ag#aagagtcc   1080aagagtccaa gcaaaactac cgtgcgatgc ctggaagctg aagtttagat ga#gacagaaa   1140tgaggagaca cacctgaggc tggtttcttt catgctcctt accctgcccc ag#ctggggaa   1200atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaac tg#gaatcagc   1260tcaggactgc cattggacta tggagtgcac caaagagaat gcccttctcc tt#attgtaac   1320cctgtctgga tcctatcctc ctacctccaa agcttcccac ggcctttcta gc#ctggctat   1380gtcctaataa tatcccactg ggagaaagga gttttgcaaa gtgcaaggac ct#aaaacatc   1440tcatcagtat ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg gg#ttgaaagc   1500caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac cc#tttcttca   1560gctctgaaag agaaacacgt atcccacctg acatgtcctt ctgagcccgg ta#agagcaaa   1620agaatggcag aaaagtttag cccctgaaag ccatggagat tctcataact tg#agacctaa   1680tctctgtaaa gctaaaataa agaaatagaa caaggctgag gatacgacag ta#cactgtca   1740gcagggactg taaacacaga cagggtcaaa gtgttttctc tgaacacatt ga#gttggaat   1800cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga ta#ttttctct   1860aggaaatata cttttacaag taacaaaaat aaaaactctt ataaatttct at#ttttatct   1920gagttacaga aatgattact aaggaagatt actcagtaat ttgtttaaaa ag#taataaaa   1980ttcaacaaac atttgctgaa tagctactat atgtcaagtg ctgtgcaagg ta#ttacactc   2040tgtaattgaa tattattcct caaaaaattg cacatagtag aacgctatct gg#gaagctat   2100ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta tt#tttgctga   2160gactaatctt attcattttc tctaatatgg caaccattat aaccttaatt ta#ttattaac   2220atacctaaga agtacattgt tacctctata taccaaagca cattttaaaa gt#gccattaa   2280caaatgtatc actagccctc ctttttccaa caagaaggga ctgagagatg ca#gaaatatt   2340 tgtgacaaaa aattaaagca tttagaaaac tt       #                   #        2372 <210> SEQ ID NO 201 <211> LENGTH: 322<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic protein <400> SEQUENCE: 201Met Ala Arg Cys Phe Ser Leu Val Leu Leu Le #u Thr Ser Ile Trp Thr  1               5  #                 10  #                 15Thr Arg Leu Leu Val Gln Gly Ser Leu Arg Al #a Glu Glu Leu Ser Ile             20      #             25      #             30Gln Val Ser Cys Arg Ile Met Gly Ile Thr Le #u Val Ser Lys Lys Ala         35          #         40          #         45Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Gl #u Ala Cys Arg Leu Leu     50              #     55              #     60Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Gl #u Thr Ala Leu Lys Ala 65                  # 70                  # 75                  # 80Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val Gl #y Asp Gly Phe Val Val                 85  #                 90  #                 95Ile Ser Arg Ile Ser Pro Asn Pro Lys Cys Gl #y Lys Asn Gly Val Gly            100       #           105       #           110Val Leu Ile Trp Lys Val Pro Val Ser Arg Gl #n Phe Ala Ala Tyr Cys        115           #       120           #       125Tyr Asn Ser Ser Asp Thr Trp Thr Asn Ser Cy #s Ile Pro Glu Ile Ile    130               #   135               #   140Thr Thr Lys Asp Pro Ile Phe Asn Thr Gln Th #r Ala Thr Gln Thr Thr145                 1 #50                 1 #55                 1 #60Glu Phe Ile Val Ser Asp Ser Thr Tyr Ser Va #l Ala Ser Pro Tyr Ser                165   #               170   #               175Thr Ile Pro Ala Pro Thr Thr Thr Pro Pro Al #a Pro Ala Ser Thr Ser            180       #           185       #           190Ile Pro Arg Arg Lys Lys Leu Ile Cys Val Th #r Glu Val Phe Met Glu        195           #       200           #       205Thr Ser Thr Met Ser Thr Glu Thr Glu Pro Ph #e Val Glu Asn Lys Ala    210               #   215               #   220Ala Phe Lys Asn Glu Ala Ala Gly Phe Gly Gl #y Val Pro Thr Ala Leu225                 2 #30                 2 #35                 2 #40Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Al #a Ala Gly Leu Gly Phe                245   #               250   #               255Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pr #o Phe Thr Asn Lys Asn            260       #           265       #           270Gln Gln Lys Glu Met Ile Glu Thr Lys Val Va #l Lys Glu Glu Lys Ala        275           #       280           #       285Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Ly #s Thr Asp Lys Asn Pro    290               #   295               #   300Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Va #l Arg Cys Leu Glu Ala305                 3 #10                 3 #15                 3 #20Glu Val <210> SEQ ID NO 202 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 202gagctttcca tccaggtgtc atgc           #                  #                24 <210> SEQ ID NO 203 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 203gtcagtgaca gtacctactc gg            #                  #                 22 <210> SEQ ID NO 204 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 204tggagcagga ggagtagtag tagg           #                  #                24 <210> SEQ ID NO 205 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 205aggaggcctg taggctgctg ggactaagtt tggccggcaa ggaccaagtt  #              50 <210> SEQ ID NO 206 <211> LENGTH: 1620 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: (973)<223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base<222> LOCATION: (977) <223> OTHER INFORMATION: a, t, c or g<221> NAME/KEY: modified_base <222> LOCATION: (996)<223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base<222> LOCATION: (1003) <223> OTHER INFORMATION: a, t, c or g<400> SEQUENCE: 206agatggcggt cttggcacct ctaattgctc tcgtgtattc ggtgccgcga ct#ttcacgat     60ggctcgccca accttactac cttctgtcgg ccctgctctc tgctgccttc ct#actcgtga    120ggaaactgcc gccgctctgc cacggtctgc ccacccaacg cgaagacggt aa#cccgtgtg    180actttgactg gagagaagtg gagatcctga tgtttctcag tgccattgtg at#gatgaaga    240accgcagatc catcactgtg gagcaacata taggcaacat tttcatgttt ag#taaagtgg    300ccaacacaat tcttttcttc cgcttggata ttcgcatggg cctactttac at#cacactct    360gcatagtgtt cctgatgacg tgcaaacccc ccctatatat gggccctgag ta#tatcaagt    420acttcaatga taaaaccatt gatgaggaac tagaacggga caagagggtc ac#ttggattg    480tggagttctt tgccaattgg tctaatgact gccaatcatt tgcccctatc ta#tgctgacc    540tctcccttaa atacaactgt acagggctaa attttgggaa ggtggatgtt gg#acgctata    600ctgatgttag tacgcggtac aaagtgagca catcacccct caccaagcaa ct#ccctaccc    660tgatcctgtt ccaaggtggc aaggaggcaa tgcggcggcc acagattgac aa#gaaaggac    720gggctgtctc atggaccttc tctgaggaga atgtgatccg agaatttaac tt#aaatgagc    780tataccagcg ggccaagaaa ctatcaaagg ctggagacaa tatccctgag ga#gcagcctg    840tggcttcaac ccccaccaca gtgtcagatg gggaaaacaa gaaggataaa ta#agatcctc    900actttggcag tgcttcctct cctgtcaatt ccaggctctt tccataacca ca#agcctgag    960gctgcagcct ttnattnatg ttttcccttt ggctgngact ggntggggca gc#atgcagct   1020tctgatttta aagaggcatc tagggaattg tcaggcaccc tacaggaagg cc#tgccatgc   1080tgtggccaac tgtttcactg gagcaagaaa gagatctcat aggacggagg gg#gaaatggt   1140ttccctccaa gcttgggtca gtgtgttaac tgcttatcag ctattcagac at#ctccatgg   1200tttctccatg aaactctgtg gtttcatcat tccttcttag ttgacctgca ca#gcttggtt   1260agacctagat ttaaccctaa ggtaagatgc tggggtatag aacgctaaga at#tttccccc   1320aaggactctt gcttccttaa gcccttctgg cttcgtttat ggtcttcatt aa#aagtataa   1380gcctaacttt gtcgctagtc ctaaggagaa acctttaacc acaaagtttt ta#tcattgaa   1440gacaatattg aacaaccccc tattttgtgg ggattgagaa ggggtgaata ga#ggcttgag   1500actttccttt gtgtggtagg acttggagga gaaatcccct ggactttcac ta#accctctg   1560acatactccc cacacccagt tgatggcttt ccgtaataaa aagattggga tt#tccttttg   1620 <210> SEQ ID NO 207 <211> LENGTH: 296 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 207Met Ala Val Leu Ala Pro Leu Ile Ala Leu Va #l Tyr Ser Val Pro Arg  1               5  #                 10  #                 15Leu Ser Arg Trp Leu Ala Gln Pro Tyr Tyr Le #u Leu Ser Ala Leu Leu             20      #             25      #             30Ser Ala Ala Phe Leu Leu Val Arg Lys Leu Pr #o Pro Leu Cys His Gly         35          #         40          #         45Leu Pro Thr Gln Arg Glu Asp Gly Asn Pro Cy #s Asp Phe Asp Trp Arg     50              #     55              #     60Glu Val Glu Ile Leu Met Phe Leu Ser Ala Il #e Val Met Met Lys Asn 65                  # 70                  # 75                  # 80Arg Arg Ser Ile Thr Val Glu Gln His Ile Gl #y Asn Ile Phe Met Phe                 85  #                 90  #                 95Ser Lys Val Ala Asn Thr Ile Leu Phe Phe Ar #g Leu Asp Ile Arg Met            100       #           105       #           110Gly Leu Leu Tyr Ile Thr Leu Cys Ile Val Ph #e Leu Met Thr Cys Lys        115           #       120           #       125Pro Pro Leu Tyr Met Gly Pro Glu Tyr Ile Ly #s Tyr Phe Asn Asp Lys    130               #   135               #   140Thr Ile Asp Glu Glu Leu Glu Arg Asp Lys Ar #g Val Thr Trp Ile Val145                 1 #50                 1 #55                 1 #60Glu Phe Phe Ala Asn Trp Ser Asn Asp Cys Gl #n Ser Phe Ala Pro Ile                165   #               170   #               175Tyr Ala Asp Leu Ser Leu Lys Tyr Asn Cys Th #r Gly Leu Asn Phe Gly            180       #           185       #           190Lys Val Asp Val Gly Arg Tyr Thr Asp Val Se #r Thr Arg Tyr Lys Val        195           #       200           #       205Ser Thr Ser Pro Leu Thr Lys Gln Leu Pro Th #r Leu Ile Leu Phe Gln    210               #   215               #   220Gly Gly Lys Glu Ala Met Arg Arg Pro Gln Il #e Asp Lys Lys Gly Arg225                 2 #30                 2 #35                 2 #40Ala Val Ser Trp Thr Phe Ser Glu Glu Asn Va #l Ile Arg Glu Phe Asn                245   #               250   #               255Leu Asn Glu Leu Tyr Gln Arg Ala Lys Lys Le #u Ser Lys Ala Gly Asp            260       #           265       #           270Asn Ile Pro Glu Glu Gln Pro Val Ala Ser Th #r Pro Thr Thr Val Ser        275           #       280           #       285Asp Gly Glu Asn Lys Lys Asp Lys     290               #   295<210> SEQ ID NO 208 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 208gcttggatat tcgcatgggc ctac           #                  #                24 <210> SEQ ID NO 209 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 209tggagacaat atccctgagg             #                  #                   # 20 <210> SEQ ID NO 210 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 210aacagttggc cacagcatgg cagg           #                  #                24 <210> SEQ ID NO 211 <211> LENGTH: 50 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 211ccattgatga ggaactagaa cgggacaaga gggtcacttg gattgtggag  #              50 <210> SEQ ID NO 212 <211> LENGTH: 1985 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 212ggacagctcg cggcccccga gagctctagc cgtcgaggag ctgcctgggg ac#gtttgccc     60tggggcccca gcctggcccg ggtcaccctg gcatgaggag atgggcctgt tg#ctcctggt    120cccattgctc ctgctgcccg gctcctacgg actgcccttc tacaacggct tc#tactactc    180caacagcgcc aacgaccaga acctaggcaa cggtcatggc aaagacctcc tt#aatggagt    240gaagctggtg gtggagacac ccgaggagac cctgttcacc taccaagggg cc#agtgtgat    300cctgccctgc cgctaccgct acgagccggc cctggtctcc ccgcggcgtg tg#cgtgtcaa    360atggtggaag ctgtcggaga acggggcccc agagaaggac gtgctggtgg cc#atcgggct    420gaggcaccgc tcctttgggg actaccaagg ccgcgtgcac ctgcggcagg ac#aaagagca    480tgacgtctcg ctggagatcc aggatctgcg gctggaggac tatgggcgtt ac#cgctgtga    540ggtcattgac gggctggagg atgaaagcgg tctggtggag ctggagctgc gg#ggtgtggt    600ctttccttac cagtccccca acgggcgcta ccagttcaac ttccacgagg gc#cagcaggt    660ctgtgcagag caggctgcgg tggtggcctc ctttgagcag ctcttccggg cc#tgggagga    720gggcctggac tggtgcaacg cgggctggct gcaggatgct acggtgcagt ac#cccatcat    780gttgccccgg cagccctgcg gtggcccagg cctggcacct ggcgtgcgaa gc#tacggccc    840ccgccaccgc cgcctgcacc gctatgatgt attctgcttc gctactgccc tc#aaggggcg    900ggtgtactac ctggagcacc ctgagaagct gacgctgaca gaggcaaggg ag#gcctgcca    960ggaagatgat gccacgatcg ccaaggtggg acagctcttt gccgcctgga ag#ttccatgg   1020cctggaccgc tgcgacgctg gctggctggc agatggcagc gtccgctacc ct#gtggttca   1080cccgcatcct aactgtgggc ccccagagcc tggggtccga agctttggct tc#cccgaccc   1140gcagagccgc ttgtacggtg tttactgcta ccgccagcac taggacctgg gg#ccctcccc   1200tgccgcattc cctcactggc tgtgtattta ttgagtggtt cgttttccct tg#tgggttgg   1260agccatttta actgttttta tacttctcaa tttaaatttt ctttaaacat tt#ttttacta   1320ttttttgtaa agcaaacaga acccaatgcc tccctttgct cctggatgcc cc#actccagg   1380aatcatgctt gctcccctgg gccatttgcg gttttgtggg cttctggagg gt#tccccgcc   1440atccaggctg gtctccctcc cttaaggagg ttggtgccca gagtgggcgg tg#gcctgtct   1500agaatgccgc cgggagtccg ggcatggtgg gcacagttct ccctgcccct ca#gcctgggg   1560gaagaagagg gcctcggggg cctccggagc tgggctttgg gcctctcctg cc#cacctcta   1620cttctctgtg aagccgctga ccccagtctg cccactgagg ggctagggct gg#aagccagt   1680tctaggcttc caggcgaaat ctgagggaag gaagaaactc ccctccccgt tc#cccttccc   1740ctctcggttc caaagaatct gttttgttgt catttgtttc tcctgtttcc ct#gtgtgggg   1800aggggccctc aggtgtgtgt actttggaca ataaatggtg ctatgactgc ct#tccgccaa   1860aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa#aaaaaaaa   1920aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa#aaaaaaaa   1980 aaaaa                  #                  #                   #          1985 <210> SEQ ID NO 213<211> LENGTH: 360 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 213 Met Gly Leu Leu Leu Leu Val Pro Leu Leu Le#u Leu Pro Gly Ser Tyr   1               5  #                 10 #                 15 Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Se#r Asn Ser Ala Asn Asp              20      #             25     #             30 Gln Asn Leu Gly Asn Gly His Gly Lys Asp Le#u Leu Asn Gly Val Lys          35          #         40         #         45 Leu Val Val Glu Thr Pro Glu Glu Thr Leu Ph#e Thr Tyr Gln Gly Ala      50              #     55             #     60 Ser Val Ile Leu Pro Cys Arg Tyr Arg Tyr Gl#u Pro Ala Leu Val Ser  65                  # 70                 # 75                  # 80 Pro Arg Arg Val Arg Val Lys Trp Trp Lys Le#u Ser Glu Asn Gly Ala                  85  #                 90 #                 95 Pro Glu Lys Asp Val Leu Val Ala Ile Gly Le#u Arg His Arg Ser Phe             100       #           105      #           110 Gly Asp Tyr Gln Gly Arg Val His Leu Arg Gl#n Asp Lys Glu His Asp         115           #       120          #       125 Val Ser Leu Glu Ile Gln Asp Leu Arg Leu Gl#u Asp Tyr Gly Arg Tyr     130               #   135              #   140 Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Gl#u Ser Gly Leu Val Glu 145                 1 #50                 1#55                 1 #60 Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gl#n Ser Pro Asn Gly Arg                 165   #               170  #               175 Tyr Gln Phe Asn Phe His Glu Gly Gln Gln Va#l Cys Ala Glu Gln Ala             180       #           185      #           190 Ala Val Val Ala Ser Phe Glu Gln Leu Phe Ar#g Ala Trp Glu Glu Gly         195           #       200          #       205 Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln As#p Ala Thr Val Gln Tyr     210               #   215              #   220 Pro Ile Met Leu Pro Arg Gln Pro Cys Gly Gl#y Pro Gly Leu Ala Pro 225                 2 #30                 2#35                 2 #40 Gly Val Arg Ser Tyr Gly Pro Arg His Arg Ar#g Leu His Arg Tyr Asp                 245   #               250  #               255 Val Phe Cys Phe Ala Thr Ala Leu Lys Gly Ar#g Val Tyr Tyr Leu Glu             260       #           265      #           270 His Pro Glu Lys Leu Thr Leu Thr Glu Ala Ar#g Glu Ala Cys Gln Glu         275           #       280          #       285 Asp Asp Ala Thr Ile Ala Lys Val Gly Gln Le#u Phe Ala Ala Trp Lys     290               #   295              #   300 Phe His Gly Leu Asp Arg Cys Asp Ala Gly Tr#p Leu Ala Asp Gly Ser 305                 3 #10                 3#15                 3 #20 Val Arg Tyr Pro Val Val His Pro His Pro As#n Cys Gly Pro Pro Glu                 325   #               330  #               335 Pro Gly Val Arg Ser Phe Gly Phe Pro Asp Pr#o Gln Ser Arg Leu Tyr             340       #           345      #           350 Gly Val Tyr Cys Tyr Arg Gln His         355          #       360 <210> SEQ ID NO 214 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 214tgcttcgcta ctgccctc              #                   #                  #  18 <210> SEQ ID NO 215 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 215ttcccttgtg ggttggag              #                   #                  #  18 <210> SEQ ID NO 216 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 216agggctggaa gccagttc              #                   #                  #  18 <210> SEQ ID NO 217 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 217agccagtgag gaaatgcg              #                   #                  #  18 <210> SEQ ID NO 218 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 218tgtccaaagt acacacacct gagg           #                  #                24 <210> SEQ ID NO 219 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 219gatgccacga tcgccaaggt gggacagctc tttgccgcct ggaag    #                  #45 <210> SEQ ID NO 220 <211> LENGTH: 1503 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 220ggagagcgga gcgaagctgg ataacagggg accgatgatg tggcgaccat ca#gttctgct     60gcttctgttg ctactgaggc acggggccca ggggaagcca tccccagacg ca#ggccctca    120tggccagggg agggtgcacc aggcggcccc cctgagcgac gctccccatg at#gacgccca    180cgggaacttc cagtacgacc atgaggcttt cctgggacgg gaagtggcca ag#gaattcga    240ccaactcacc ccagaggaaa gccaggcccg tctggggcgg atcgtggacc gc#atggaccg    300cgcgggggac ggcgacggct gggtgtcgct ggccgagctt cgcgcgtgga tc#gcgcacac    360gcagcagcgg cacatacggg actcggtgag cgcggcctgg gacacgtacg ac#acggaccg    420cgacgggcgt gtgggttggg aggagctgcg caacgccacc tatggccact ac#gcgcccgg    480tgaagaattt catgacgtgg aggatgcaga gacctacaaa aagatgctgg ct#cgggacga    540gcggcgtttc cgggtggccg accaggatgg ggactcgatg gccactcgag ag#gagctgac    600agccttcctg caccccgagg agttccctca catgcgggac atcgtgattg ct#gaaaccct    660ggaggacctg gacagaaaca aagatggcta tgtccaggtg gaggagtaca tc#gcggatct    720gtactcagcc gagcctgggg aggaggagcc ggcgtgggtg cagacggaga gg#cagcagtt    780ccgggacttc cgggatctga acaaggatgg gcacctggat gggagtgagg tg#ggccactg    840ggtgctgccc cctgcccagg accagcccct ggtggaagcc aaccacctgc tg#cacgagag    900cgacacggac aaggatgggc ggctgagcaa agcggaaatc ctgggtaatt gg#aacatgtt    960tgtgggcagt caggccacca actatggcga ggacctgacc cggcaccacg at#gagctgtg   1020agcaccgcgc acctgccaca gcctcagagg cccgcacaat gaccggagga gg#ggccgctg   1080tggtctggcc ccctccctgt ccaggccccg caggaggcag atgcagtccc ag#gcatcctc   1140ctgcccctgg gctctcaggg accccctggg tcggcttctg tccctgtcac ac#ccccaacc   1200ccagggaggg gctgtcatag tcccagagga taagcaatac ctatttctga ct#gagtctcc   1260cagcccagac ccagggaccc ttggccccaa gctcagctct aagaaccgcc cc#aacccctc   1320cagctccaaa tctgagcctc caccacatag actgaaactc ccctggcccc ag#ccctctcc   1380tgcctggcct ggcctgggac acctcctctc tgccaggagg caataaaagc ca#gcgccggg   1440accttgaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa#aaaaaaaa   1500 aaa                   #                  #                   #           1503 <210> SEQ ID NO 221<211> LENGTH: 328 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 221 Met Met Trp Arg Pro Ser Val Leu Leu Leu Le#u Leu Leu Leu Arg His   1               5  #                 10 #                 15 Gly Ala Gln Gly Lys Pro Ser Pro Asp Ala Gl#y Pro His Gly Gln Gly              20      #             25     #             30 Arg Val His Gln Ala Ala Pro Leu Ser Asp Al#a Pro His Asp Asp Ala          35          #         40         #         45 His Gly Asn Phe Gln Tyr Asp His Glu Ala Ph#e Leu Gly Arg Glu Val      50              #     55             #     60 Ala Lys Glu Phe Asp Gln Leu Thr Pro Glu Gl#u Ser Gln Ala Arg Leu  65                  # 70                 # 75                  # 80 Gly Arg Ile Val Asp Arg Met Asp Arg Ala Gl#y Asp Gly Asp Gly Trp                  85  #                 90 #                 95 Val Ser Leu Ala Glu Leu Arg Ala Trp Ile Al#a His Thr Gln Gln Arg             100       #           105      #           110 His Ile Arg Asp Ser Val Ser Ala Ala Trp As#p Thr Tyr Asp Thr Asp         115           #       120          #       125 Arg Asp Gly Arg Val Gly Trp Glu Glu Leu Ar#g Asn Ala Thr Tyr Gly     130               #   135              #   140 His Tyr Ala Pro Gly Glu Glu Phe His Asp Va#l Glu Asp Ala Glu Thr 145                 1 #50                 1#55                 1 #60 Tyr Lys Lys Met Leu Ala Arg Asp Glu Arg Ar#g Phe Arg Val Ala Asp                 165   #               170  #               175 Gln Asp Gly Asp Ser Met Ala Thr Arg Glu Gl#u Leu Thr Ala Phe Leu             180       #           185      #           190 His Pro Glu Glu Phe Pro His Met Arg Asp Il#e Val Ile Ala Glu Thr         195           #       200          #       205 Leu Glu Asp Leu Asp Arg Asn Lys Asp Gly Ty#r Val Gln Val Glu Glu     210               #   215              #   220 Tyr Ile Ala Asp Leu Tyr Ser Ala Glu Pro Gl#y Glu Glu Glu Pro Ala 225                 2 #30                 2#35                 2 #40 Trp Val Gln Thr Glu Arg Gln Gln Phe Arg As#p Phe Arg Asp Leu Asn                 245   #               250  #               255 Lys Asp Gly His Leu Asp Gly Ser Glu Val Gl#y His Trp Val Leu Pro             260       #           265      #           270 Pro Ala Gln Asp Gln Pro Leu Val Glu Ala As#n His Leu Leu His Glu         275           #       280          #       285 Ser Asp Thr Asp Lys Asp Gly Arg Leu Ser Ly#s Ala Glu Ile Leu Gly     290               #   295              #   300 Asn Trp Asn Met Phe Val Gly Ser Gln Ala Th#r Asn Tyr Gly Glu Asp 305                 3 #10                 3#15                 3 #20 Leu Thr Arg His His Asp Glu Leu                325 <210> SEQ ID NO 222 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 222cgcaggccct catggccagg             #                  #                   # 20 <210> SEQ ID NO 223 <211> LENGTH: 18<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 223gaaatcctgg gtaattgg              #                   #                  #  18 <210> SEQ ID NO 224 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 224gtgcgcggtg ctcacagctc atc            #                  #                23 <210> SEQ ID NO 225 <211> LENGTH: 44 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 225cccccctgag cgacgctccc ccatgatgac gcccacggga actt    #                  # 44 <210> SEQ ID NO 226 <211> LENGTH: 2403 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 226ggggccttgc cttccgcact cgggcgcagc cgggtggatc tcgagcaggt gc#ggagcccc     60gggcggcggg cgcgggtgcg agggatccct gacgcctctg tccctgtttc tt#tgtcgctc    120ccagcctgtc tgtcgtcgtt ttggcgcccc cgcctccccg cggtgcgggg tt#gcacaccg    180atcctgggct tcgctcgatt tgccgccgag gcgcctccca gacctagagg gg#cgctggcc    240tggagcagcg ggtcgtctgt gtcctctctc ctctgcgccg cgcccgggga tc#cgaagggt    300gcggggctct gaggaggtga cgcgcggggc ctcccgcacc ctggccttgc cc#gcattctc    360cctctctccc aggtgtgagc agcctatcag tcaccatgtc cgcagcctgg at#cccggctc    420tcggcctcgg tgtgtgtctg ctgctgctgc cggggcccgc gggcagcgag gg#agccgctc    480ccattgctat cacatgtttt accagaggct tggacatcag gaaagagaaa gc#agatgtcc    540tctgcccagg gggctgccct cttgaggaat tctctgtgta tgggaacata gt#atatgctt    600ctgtatcgag catatgtggg gctgctgtcc acaggggagt aatcagcaac tc#agggggac    660ctgtacgagt ctatagccta cctggtcgag aaaactattc ctcagtagat gc#caatggca    720tccagtctca aatgctttct agatggtctg cttctttcac agtaactaaa gg#caaaagta    780gtacacagga ggccacagga caagcagtgt ccacagcaca tccaccaaca gg#taaacgac    840taaagaaaac acccgagaag aaaactggca ataaagattg taaagcagac at#tgcatttc    900tgattgatgg aagctttaat attgggcagc gccgatttaa tttacagaag aa#ttttgttg    960gaaaagtggc tctaatgttg ggaattggaa cagaaggacc acatgtgggc ct#tgttcaag   1020ccagtgaaca tcccaaaata gaattttact tgaaaaactt tacatcagcc aa#agatgttt   1080tgtttgccat aaaggaagta ggtttcagag ggggtaattc caatacagga aa#agccttga   1140agcatactgc tcagaaattc ttcacggtag atgctggagt aagaaaaggg at#ccccaaag   1200tggtggtggt atttattgat ggttggcctt ctgatgacat cgaggaagca gg#cattgtgg   1260ccagagagtt tggtgtcaat gtatttatag tttctgtggc caagcctatc cc#tgaagaac   1320tggggatggt tcaggatgtc acatttgttg acaaggctgt ctgtcggaat aa#tggcttct   1380tctcttacca catgcccaac tggtttggca ccacaaaata cgtaaagcct ct#ggtacaga   1440agctgtgcac tcatgaacaa atgatgtgca gcaagacctg ttataactca gt#gaacattg   1500cctttctaat tgatggctcc agcagtgttg gagatagcaa tttccgcctc at#gcttgaat   1560ttgtttccaa catagccaag acttttgaaa tctcggacat tggtgccaag at#agctgctg   1620tacagtttac ttatgatcag cgcacggagt tcagtttcac tgactatagc ac#caaagaga   1680atgtcctagc tgtcatcaga aacatccgct atatgagtgg tggaacagct ac#tggtgatg   1740ccatttcctt cactgttaga aatgtgtttg gccctataag ggagagcccc aa#caagaact   1800tcctagtaat tgtcacagat gggcagtcct atgatgatgt ccaaggccct gc#agctgctg   1860cacatgatgc aggaatcact atcttctctg ttggtgtggc ttgggcacct ct#ggatgacc   1920tgaaagatat ggcttctaaa ccgaaggagt ctcacgcttt cttcacaaga ga#gttcacag   1980gattagaacc aattgtttct gatgtcatca gaggcatttg tagagatttc tt#agaatccc   2040agcaataatg gtaacatttt gacaactgaa agaaaaagta caaggggatc ca#gtgtgtaa   2100attgtattct cataatactg aaatgcttta gcatactaga atcagataca aa#actattaa   2160gtatgtcaac agccatttag gcaaataagc actcctttaa agccgctgcc tt#ctggttac   2220aatttacagt gtactttgtt aaaaacactg ctgaggcttc ataatcatgg ct#cttagaaa   2280ctcaggaaag aggagataat gtggattaaa accttaagag ttctaaccat gc#ctactaaa   2340tgtacagata tgcaaattcc atagctcaat aaaagaatct gatacttaga cc#aaaaaaaa   2400 aaa                   #                  #                   #           2403 <210> SEQ ID NO 227<211> LENGTH: 550 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 227 Met Ser Ala Ala Trp Ile Pro Ala Leu Gly Le#u Gly Val Cys Leu Leu   1               5  #                 10 #                 15 Leu Leu Pro Gly Pro Ala Gly Ser Glu Gly Al#a Ala Pro Ile Ala Ile              20      #             25     #             30 Thr Cys Phe Thr Arg Gly Leu Asp Ile Arg Ly#s Glu Lys Ala Asp Val          35          #         40         #         45 Leu Cys Pro Gly Gly Cys Pro Leu Glu Glu Ph#e Ser Val Tyr Gly Asn      50              #     55             #     60 Ile Val Tyr Ala Ser Val Ser Ser Ile Cys Gl#y Ala Ala Val His Arg  65                  # 70                 # 75                  # 80 Gly Val Ile Ser Asn Ser Gly Gly Pro Val Ar#g Val Tyr Ser Leu Pro                  85  #                 90 #                 95 Gly Arg Glu Asn Tyr Ser Ser Val Asp Ala As#n Gly Ile Gln Ser Gln             100       #           105      #           110 Met Leu Ser Arg Trp Ser Ala Ser Phe Thr Va#l Thr Lys Gly Lys Ser         115           #       120          #       125 Ser Thr Gln Glu Ala Thr Gly Gln Ala Val Se#r Thr Ala His Pro Pro     130               #   135              #   140 Thr Gly Lys Arg Leu Lys Lys Thr Pro Glu Ly#s Lys Thr Gly Asn Lys 145                 1 #50                 1#55                 1 #60 Asp Cys Lys Ala Asp Ile Ala Phe Leu Ile As#p Gly Ser Phe Asn Ile                 165   #               170  #               175 Gly Gln Arg Arg Phe Asn Leu Gln Lys Asn Ph#e Val Gly Lys Val Ala             180       #           185      #           190 Leu Met Leu Gly Ile Gly Thr Glu Gly Pro Hi#s Val Gly Leu Val Gln         195           #       200          #       205 Ala Ser Glu His Pro Lys Ile Glu Phe Tyr Le#u Lys Asn Phe Thr Ser     210               #   215              #   220 Ala Lys Asp Val Leu Phe Ala Ile Lys Glu Va#l Gly Phe Arg Gly Gly 225                 2 #30                 2#35                 2 #40 Asn Ser Asn Thr Gly Lys Ala Leu Lys His Th#r Ala Gln Lys Phe Phe                 245   #               250  #               255 Thr Val Asp Ala Gly Val Arg Lys Gly Ile Pr#o Lys Val Val Val Val             260       #           265      #           270 Phe Ile Asp Gly Trp Pro Ser Asp Asp Ile Gl#u Glu Ala Gly Ile Val         275           #       280          #       285 Ala Arg Glu Phe Gly Val Asn Val Phe Ile Va#l Ser Val Ala Lys Pro     290               #   295              #   300 Ile Pro Glu Glu Leu Gly Met Val Gln Asp Va#l Thr Phe Val Asp Lys 305                 3 #10                 3#15                 3 #20 Ala Val Cys Arg Asn Asn Gly Phe Phe Ser Ty#r His Met Pro Asn Trp                 325   #               330  #               335 Phe Gly Thr Thr Lys Tyr Val Lys Pro Leu Va#l Gln Lys Leu Cys Thr             340       #           345      #           350 His Glu Gln Met Met Cys Ser Lys Thr Cys Ty#r Asn Ser Val Asn Ile         355           #       360          #       365 Ala Phe Leu Ile Asp Gly Ser Ser Ser Val Gl#y Asp Ser Asn Phe Arg     370               #   375              #   380 Leu Met Leu Glu Phe Val Ser Asn Ile Ala Ly#s Thr Phe Glu Ile Ser 385                 3 #90                 3#95                 4 #00 Asp Ile Gly Ala Lys Ile Ala Ala Val Gln Ph#e Thr Tyr Asp Gln Arg                 405   #               410  #               415 Thr Glu Phe Ser Phe Thr Asp Tyr Ser Thr Ly#s Glu Asn Val Leu Ala             420       #           425      #           430 Val Ile Arg Asn Ile Arg Tyr Met Ser Gly Gl#y Thr Ala Thr Gly Asp         435           #       440          #       445 Ala Ile Ser Phe Thr Val Arg Asn Val Phe Gl#y Pro Ile Arg Glu Ser     450               #   455              #   460 Pro Asn Lys Asn Phe Leu Val Ile Val Thr As#p Gly Gln Ser Tyr Asp 465                 4 #70                 4#75                 4 #80 Asp Val Gln Gly Pro Ala Ala Ala Ala His As#p Ala Gly Ile Thr Ile                 485   #               490  #               495 Phe Ser Val Gly Val Ala Trp Ala Pro Leu As#p Asp Leu Lys Asp Met             500       #           505      #           510 Ala Ser Lys Pro Lys Glu Ser His Ala Phe Ph#e Thr Arg Glu Phe Thr         515           #       520          #       525 Gly Leu Glu Pro Ile Val Ser Asp Val Ile Ar#g Gly Ile Cys Arg Asp     530               #   535              #   540 Phe Leu Glu Ser Gln Gln 545                 5 #50<210> SEQ ID NO 228 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 228tggtctcgca caccgatc              #                   #                  #  18 <210> SEQ ID NO 229 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 229ctgctgtcca caggggag              #                   #                  #  18 <210> SEQ ID NO 230 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 230ccttgaagca tactgctc              #                   #                  #  18 <210> SEQ ID NO 231 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 231gagatagcaa tttccgcc              #                   #                  #  18 <210> SEQ ID NO 232 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 232ttcctcaaga gggcagcc              #                   #                  #  18 <210> SEQ ID NO 233 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 233cttggcacca atgtccgaga tttc           #                  #                24 <210> SEQ ID NO 234 <211> LENGTH: 45 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic      oligonucleotide probe <400> SEQUENCE: 234gctctgagga aggtgacgcg cggggcctcc gaacccttgg ccttg    #                  #45 <210> SEQ ID NO 235 <211> LENGTH: 2586 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 235cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg ca#cccgcagc     60ccggcggcct cccggcggga gcgagcagat ccagtccggc ccgcagcgca ac#tcggtcca    120gtcggggcgg cggctgcggg cgcagagcgg agatgcagcg gcttggggcc ac#cctgctgt    180gcctgctgct ggcggcggcg gtccccacgg cccccgcgcc cgctccgacg gc#gacctcgg    240ctccagtcaa gcccggcccg gctctcagct acccgcagga ggaggccacc ct#caatgaga    300tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc ag#cgcggtgg    360aagagatgga ggcagaagaa gctgctgcta aagcatcatc agaagtgaac ct#ggcaaact    420tacctcccag ctatcacaat gagaccaaca cagacacgaa ggttggaaat aa#taccatcc    480atgtgcaccg agaaattcac aagataacca acaaccagac tggacaaatg gt#cttttcag    540agacagttat cacatctgtg ggagacgaag aaggcagaag gagccacgag tg#catcatcg    600acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac ac#ctgccagc    660catgccgggg ccagaggatg ctctgcaccc gggacagtga gtgctgtgga ga#ccagctgt    720gtgtctgggg tcactgcacc aaaatggcca ccaggggcag caatgggacc at#ctgtgaca    780accagaggga ctgccagccg gggctgtgct gtgccttcca gagaggcctg ct#gttccctg    840tgtgcacacc cctgcccgtg gagggcgagc tttgccatga ccccgccagc cg#gcttctgg    900acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct tg#tgccagtg    960gcctcctctg ccagccccac agccacagcc tggtgtatgt gtgcaagccg ac#cttcgtgg   1020ggagccgtga ccaagatggg gagatcctgc tgcccagaga ggtccccgat ga#gtatgaag   1080ttggcagctt catggaggag gtgcgccagg agctggagga cctggagagg ag#cctgactg   1140aagagatggc gctgggggag cctgcggctg ccgccgctgc actgctggga gg#ggaagaga   1200tttagatctg gaccaggctg tgggtagatg tgcaatagaa atagctaatt ta#tttcccca   1260ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta catcttcttc cc#agtaagtt   1320tcccctctgg cttgacagca tgaggtgttg tgcatttgtt cagctccccc ag#gctgttct   1380ccaggcttca cagtctggtg cttgggagag tcaggcaggg ttaaactgca gg#agcagttt   1440gccacccctg tccagattat tggctgcttt gcctctacca gttggcagac ag#ccgtttgt   1500tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtgg ag#tctccctc   1560tgattggttt tggggaaatg tggagaagag tgccctgctt tgcaaacatc aa#cctggcaa   1620aaatgcaaca aatgaatttt ccacgcagtt ctttccatgg gcataggtaa gc#tgtgcctt   1680cagctgttgc agatgaaatg ttctgttcac cctgcattac atgtgtttat tc#atccagca   1740gtgttgctca gctcctacct ctgtgccagg gcagcatttt catatccaag at#caattccc   1800tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg ga#tctcagag   1860gctcagagac tgcaagctgc ttgcccaagt cacacagcta gtgaagacca ga#gcagtttc   1920atctggttgt gactctaagc tcagtgctct ctccactacc ccacaccagc ct#tggtgcca   1980ccaaaagtgc tccccaaaag gaaggagaat gggatttttc ttgaggcatg ca#catctgga   2040attaaggtca aactaattct cacatccctc taaaagtaaa ctactgttag ga#acagcagt   2100gttctcacag tgtggggcag ccgtccttct aatgaagaca atgatattga ca#ctgtccct   2160ctttggcagt tgcattagta actttgaaag gtatatgact gagcgtagca ta#caggttaa   2220cctgcagaaa cagtacttag gtaattgtag ggcgaggatt ataaatgaaa tt#tgcaaaat   2280cacttagcag caactgaaga caattatcaa ccacgtggag aaaatcaaac cg#agcagggc   2340tgtgtgaaac atggttgtaa tatgcgactg cgaacactga actctacgcc ac#tccacaaa   2400tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt tc#ttaaagtt   2460taaagttgca catgattgta taagcatgct ttctttgagt tttaaattat gt#ataaacat   2520aagttgcatt tagaaatcaa gcataaatca cttcaactgc aaaaaaaaaa aa#aaaaaaaa   2580 aaaaaa                  #                  #                   #         2586 <210> SEQ ID NO 236 <211> LENGTH: 350<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 236Met Gln Arg Leu Gly Ala Thr Leu Leu Cys Le #u Leu Leu Ala Ala Ala  1               5  #                 10  #                 15Val Pro Thr Ala Pro Ala Pro Ala Pro Thr Al #a Thr Ser Ala Pro Val             20      #             25      #             30Lys Pro Gly Pro Ala Leu Ser Tyr Pro Gln Gl #u Glu Ala Thr Leu Asn         35          #         40          #         45Glu Met Phe Arg Glu Val Glu Glu Leu Met Gl #u Asp Thr Gln His Lys     50              #     55              #     60Leu Arg Ser Ala Val Glu Glu Met Glu Ala Gl #u Glu Ala Ala Ala Lys 65                  # 70                  # 75                  # 80Ala Ser Ser Glu Val Asn Leu Ala Asn Leu Pr #o Pro Ser Tyr His Asn                 85  #                 90  #                 95Glu Thr Asn Thr Asp Thr Lys Val Gly Asn As #n Thr Ile His Val His            100       #           105       #           110Arg Glu Ile His Lys Ile Thr Asn Asn Gln Th #r Gly Gln Met Val Phe        115           #       120           #       125Ser Glu Thr Val Ile Thr Ser Val Gly Asp Gl #u Glu Gly Arg Arg Ser    130               #   135               #   140His Glu Cys Ile Ile Asp Glu Asp Cys Gly Pr #o Ser Met Tyr Cys Gln145                 1 #50                 1 #55                 1 #60Phe Ala Ser Phe Gln Tyr Thr Cys Gln Pro Cy #s Arg Gly Gln Arg Met                165   #               170   #               175Leu Cys Thr Arg Asp Ser Glu Cys Cys Gly As #p Gln Leu Cys Val Trp            180       #           185       #           190Gly His Cys Thr Lys Met Ala Thr Arg Gly Se #r Asn Gly Thr Ile Cys        195           #       200           #       205Asp Asn Gln Arg Asp Cys Gln Pro Gly Leu Cy #s Cys Ala Phe Gln Arg    210               #   215               #   220Gly Leu Leu Phe Pro Val Cys Thr Pro Leu Pr #o Val Glu Gly Glu Leu225                 2 #30                 2 #35                 2 #40Cys His Asp Pro Ala Ser Arg Leu Leu Asp Le #u Ile Thr Trp Glu Leu                245   #               250   #               255Glu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cy #s Ala Ser Gly Leu Leu            260       #           265       #           270Cys Gln Pro His Ser His Ser Leu Val Tyr Va #l Cys Lys Pro Thr Phe        275           #       280           #       285Val Gly Ser Arg Asp Gln Asp Gly Glu Ile Le #u Leu Pro Arg Glu Val    290               #   295               #   300Pro Asp Glu Tyr Glu Val Gly Ser Phe Met Gl #u Glu Val Arg Gln Glu305                 3 #10                 3 #15                 3 #20Leu Glu Asp Leu Glu Arg Ser Leu Thr Glu Gl #u Met Ala Leu Gly Glu                325   #               330   #               335Pro Ala Ala Ala Ala Ala Ala Leu Leu Gly Gl #y Glu Glu Ile            340       #           345       #           350<210> SEQ ID NO 237 <211> LENGTH: 17 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe<400> SEQUENCE: 237 ggagctgcac cccttgc              #                  #                   #   17 <210> SEQ ID NO 238 <211> LENGTH: 49<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 238ggaggactgt gccaccatga gagactcttc aaacccaagg caaaattgg  #              49 <210> SEQ ID NO 239 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 239 gcagagcgga gatgcagcgg cttg          #                   #               24 <210> SEQ ID NO 240<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 240 ttggcagctt catggagg             #                   #                   # 18 <210> SEQ ID NO 241<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 241 cctgggcaaa aatgcaac             #                   #                   # 18 <210> SEQ ID NO 242<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 242 ctccagctcc tggcgcacct cctc          #                   #                24 <210> SEQ ID NO 243<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 243ggctctcagc taccgcgcag gagcgaggcc accctcaatg agatg    #                  #45 <210> SEQ ID NO 244 <211> LENGTH: 3679 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 244aaggaggctg ggaggaaaga ggtaagaaag gttagagaac ctacctcaca  #              50tctctctggg ctcagaagga ctctgaagat aacaataatt tcagcccatc  #             100cactctcctt ccctcccaaa cacacatgtg catgtacaca cacacataca  #             150cacacataca ccttcctctc cttcactgaa gactcacagt cactcactct  #             200gtgagcaggt catagaaaag gacactaaag ccttaaggac aggcctggcc  #             250attacctctg cagctccttt ggcttgttga gtcaaaaaac atgggagggg  #             300ccaggcacgg tgactcacac ctgtaatccc agcattttgg gagaccgagg  #             350tgagcagatc acttgaggtc aggagttcga gaccagcctg gccaacatgg  #             400agaaaccccc atctctacta aaaatacaaa aattagccag gagtggtggc  #             450aggtgcctgt aatcccagct actcaggtgg ctgagccagg agaatcgctt  #             500gaatccagga ggcggaggat gcagtcagct gagtgcaccg ctgcactcca  #             550gcctgggtga cagaatgaga ctctgtctca aacaaacaaa cacgggagga  #             600ggggtagata ctgcttctct gcaacctcct taactctgca tcctcttctt  #             650ccagggctgc ccctgatggg gcctggcaat gactgagcag gcccagcccc  #             700agaggacaag gaagagaagg catattgagg agggcaagaa gtgacgcccg  #             750gtgtagaatg actgccctgg gagggtggtt ccttgggccc tggcagggtt  #             800gctgaccctt accctgcaaa acacaaagag caggactcca gactctcctt  #             850gtgaatggtc ccctgccctg cagctccacc atgaggcttc tcgtggcccc  #             900actcttgcta gcttgggtgg ctggtgccac tgccactgtg cccgtggtac  #             950cctggcatgt tccctgcccc cctcagtgtg cctgccagat ccggccctgg  #            1000tatacgcccc gctcgtccta ccgcgaggct accactgtgg actgcaatga  #            1050cctattcctg acggcagtcc ccccggcact ccccgcaggc acacagaccc  #            1100tgctcctgca gagcaacagc attgtccgtg tggaccagag tgagctgggc  #            1150tacctggcca atctcacaga gctggacctg tcccagaaca gcttttcgga  #            1200tgcccgagac tgtgatttcc atgccctgcc ccagctgctg agcctgcacc  #            1250tagaggagaa ccagctgacc cggctggagg accacagctt tgcagggctg  #            1300gccagcctac aggaactcta tctcaaccac aaccagctct accgcatcgc  #            1350ccccagggcc ttttctggcc tcagcaactt gctgcggctg cacctcaact  #            1400ccaacctcct gagggccatt gacagccgct ggtttgaaat gctgcccaac  #            1450ttggagatac tcatgattgg cggcaacaag gtagatgcca tcctggacat  #            1500gaacttccgg cccctggcca acctgcgtag cctggtgcta gcaggcatga  #            1550acctgcggga gatctccgac tatgccctgg aggggctgca aagcctggag  #            1600agcctctcct tctatgacaa ccagctggcc cgggtgccca ggcgggcact  #            1650ggaacaggtg cccgggctca agttcctaga cctcaacaag aacccgctcc  #            1700agcgggtagg gccgggggac tttgccaaca tgctgcacct taaggagctg  #            1750ggactgaaca acatggagga gctggtctcc atcgacaagt ttgccctggt  #            1800gaacctcccc gagctgacca agctggacat caccaataac ccacggctgt  #            1850ccttcatcca cccccgcgcc ttccaccacc tgccccagat ggagaccctc  #            1900atgctcaaca acaacgctct cagtgccttg caccagcaga cggtggagtc  #            1950cctgcccaac ctgcaggagg taggtctcca cggcaacccc atccgctgtg  #            2000actgtgtcat ccgctgggcc aatgccacgg gcacccgtgt ccgcttcatc  #            2050gagccgcaat ccaccctgtg tgcggagcct ccggacctcc agcgcctccc  #            2100ggtccgtgag gtgcccttcc gggagatgac ggaccactgt ttgcccctca  #            2150tctccccacg aagcttcccc ccaagcctcc aggtagccag tggagagagc  #            2200atggtgctgc attgccgggc actggccgaa cccgaacccg agatctactg  #            2250ggtcactcca gctgggcttc gactgacacc tgcccatgca ggcaggaggt  #            2300accgggtgta ccccgagggg accctggagc tgcggagggt gacagcagaa  #            2350gaggcagggc tatacacctg tgtggcccag aacctggtgg gggctgacac  #            2400taagacggtt agtgtggttg tgggccgtgc tctcctccag ccaggcaggg  #            2450acgaaggaca ggggctggag ctccgggtgc aggagaccca cccctatcac  #            2500atcctgctat cttgggtcac cccacccaac acagtgtcca ccaacctcac  #            2550ctggtccagt gcctcctccc tccggggcca gggggccaca gctctggccc  #            2600gcctgcctcg gggaacccac agctacaaca ttacccgcct ccttcaggcc  #            2650acggagtact gggcctgcct gcaagtggcc tttgctgatg cccacaccca  #            2700gttggcttgt gtatgggcca ggaccaaaga ggccacttct tgccacagag  #            2750ccttagggga tcgtcctggg ctcattgcca tcctggctct cgctgtcctt  #            2800ctcctggcag ctgggctagc ggcccacctt ggcacaggcc aacccaggaa  #            2850gggtgtgggt gggaggcggc ctctccctcc agcctgggct ttctggggct  #            2900ggagtgcccc ttctgtccgg gttgtgtctg ctcccctcgt cctgccctgg  #            2950aatccaggga ggaagctgcc cagatcctca gaaggggaga cactgttgcc  #            3000accattgtct caaaattctt gaagctcagc ctgttctcag cagtagagaa  #            3050atcactagga ctacttttta ccaaaagaga agcagtctgg gccagatgcc  #            3100ctgccaggaa agggacatgg acccacgtgc ttgaggcctg gcagctgggc  #            3150caagacagat ggggctttgt ggccctgggg gtgcttctgc agccttgaaa  #            3200aagttgccct tacctcctag ggtcacctct gctgccattc tgaggaacat  #            3250ctccaaggaa caggagggac tttggctaga gcctcctgcc tccccatctt  #            3300ctctctgccc agaggctcct gggcctggct tggctgtccc ctacctgtgt  #            3350ccccgggctg caccccttcc tcttctcttt ctctgtacag tctcagttgc  #            3400ttgctcttgt gcctcctggg caagggctga aggaggccac tccatctcac  #            3450ctcggggggc tgccctcaat gtgggagtga ccccagccag atctgaagga  #            3500catttgggag agggatgccc aggaacgcct catctcagca gcctgggctc  #            3550ggcattccga agctgacttt ctataggcaa ttttgtacct ttgtggagaa  #            3600atgtgtcacc tcccccaacc cgattcactc ttttctcctg ttttgtaaaa  #            3650 aataaaaata aataataaca ataaaaaaa         #                   #          3679 <210> SEQ ID NO 245<211> LENGTH: 713 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 245 Met Arg Leu Leu Val Ala Pro Leu Leu Leu Al#a Trp Val Ala Gly   1               5  #                 10 #                 15 Ala Thr Ala Thr Val Pro Val Val Pro Trp Hi#s Val Pro Cys Pro                  20  #                 25 #                 30 Pro Gln Cys Ala Cys Gln Ile Arg Pro Trp Ty#r Thr Pro Arg Ser                  35  #                 40 #                 45 Ser Tyr Arg Glu Ala Thr Thr Val Asp Cys As#n Asp Leu Phe Leu                  50  #                 55 #                 60 Thr Ala Val Pro Pro Ala Leu Pro Ala Gly Th#r Gln Thr Leu Leu                  65  #                 70 #                 75 Leu Gln Ser Asn Ser Ile Val Arg Val Asp Gl#n Ser Glu Leu Gly                  80  #                 85 #                 90 Tyr Leu Ala Asn Leu Thr Glu Leu Asp Leu Se#r Gln Asn Ser Phe                  95  #                100 #                105 Ser Asp Ala Arg Asp Cys Asp Phe His Ala Le#u Pro Gln Leu Leu                 110   #               115  #               120 Ser Leu His Leu Glu Glu Asn Gln Leu Thr Ar#g Leu Glu Asp His                 125   #               130  #               135 Ser Phe Ala Gly Leu Ala Ser Leu Gln Glu Le#u Tyr Leu Asn His                 140   #               145  #               150 Asn Gln Leu Tyr Arg Ile Ala Pro Arg Ala Ph#e Ser Gly Leu Ser                 155   #               160  #               165 Asn Leu Leu Arg Leu His Leu Asn Ser Asn Le#u Leu Arg Ala Ile                 170   #               175  #               180 Asp Ser Arg Trp Phe Glu Met Leu Pro Asn Le#u Glu Ile Leu Met                 185   #               190  #               195 Ile Gly Gly Asn Lys Val Asp Ala Ile Leu As#p Met Asn Phe Arg                 200   #               205  #               210 Pro Leu Ala Asn Leu Arg Ser Leu Val Leu Al#a Gly Met Asn Leu                 215   #               220  #               225 Arg Glu Ile Ser Asp Tyr Ala Leu Glu Gly Le#u Gln Ser Leu Glu                 230   #               235  #               240 Ser Leu Ser Phe Tyr Asp Asn Gln Leu Ala Ar#g Val Pro Arg Arg                 245   #               250  #               255 Ala Leu Glu Gln Val Pro Gly Leu Lys Phe Le#u Asp Leu Asn Lys                 260   #               265  #               270 Asn Pro Leu Gln Arg Val Gly Pro Gly Asp Ph#e Ala Asn Met Leu                 275   #               280  #               285 His Leu Lys Glu Leu Gly Leu Asn Asn Met Gl#u Glu Leu Val Ser                 290   #               295  #               300 Ile Asp Lys Phe Ala Leu Val Asn Leu Pro Gl#u Leu Thr Lys Leu                 305   #               310  #               315 Asp Ile Thr Asn Asn Pro Arg Leu Ser Phe Il#e His Pro Arg Ala                 320   #               325  #               330 Phe His His Leu Pro Gln Met Glu Thr Leu Me#t Leu Asn Asn Asn                 335   #               340  #               345 Ala Leu Ser Ala Leu His Gln Gln Thr Val Gl#u Ser Leu Pro Asn                 350   #               355  #               360 Leu Gln Glu Val Gly Leu His Gly Asn Pro Il#e Arg Cys Asp Cys                 365   #               370  #               375 Val Ile Arg Trp Ala Asn Ala Thr Gly Thr Ar#g Val Arg Phe Ile                 380   #               385  #               390 Glu Pro Gln Ser Thr Leu Cys Ala Glu Pro Pr#o Asp Leu Gln Arg                 395   #               400  #               405 Leu Pro Val Arg Glu Val Pro Phe Arg Glu Me#t Thr Asp His Cys                 410   #               415  #               420 Leu Pro Leu Ile Ser Pro Arg Ser Phe Pro Pr#o Ser Leu Gln Val                 425   #               430  #               435 Ala Ser Gly Glu Ser Met Val Leu His Cys Ar#g Ala Leu Ala Glu                 440   #               445  #               450 Pro Glu Pro Glu Ile Tyr Trp Val Thr Pro Al#a Gly Leu Arg Leu                 455   #               460  #               465 Thr Pro Ala His Ala Gly Arg Arg Tyr Arg Va#l Tyr Pro Glu Gly                 470   #               475  #               480 Thr Leu Glu Leu Arg Arg Val Thr Ala Glu Gl#u Ala Gly Leu Tyr                 485   #               490  #               495 Thr Cys Val Ala Gln Asn Leu Val Gly Ala As#p Thr Lys Thr Val                 500   #               505  #               510 Ser Val Val Val Gly Arg Ala Leu Leu Gln Pr#o Gly Arg Asp Glu                 515   #               520  #               525 Gly Gln Gly Leu Glu Leu Arg Val Gln Glu Th#r His Pro Tyr His                 530   #               535  #               540 Ile Leu Leu Ser Trp Val Thr Pro Pro Asn Th#r Val Ser Thr Asn                 545   #               550  #               555 Leu Thr Trp Ser Ser Ala Ser Ser Leu Arg Gl#y Gln Gly Ala Thr                 560   #               565  #               570 Ala Leu Ala Arg Leu Pro Arg Gly Thr His Se#r Tyr Asn Ile Thr                 575   #               580  #               585 Arg Leu Leu Gln Ala Thr Glu Tyr Trp Ala Cy#s Leu Gln Val Ala                 590   #               595  #               600 Phe Ala Asp Ala His Thr Gln Leu Ala Cys Va#l Trp Ala Arg Thr                 605   #               610  #               615 Lys Glu Ala Thr Ser Cys His Arg Ala Leu Gl#y Asp Arg Pro Gly                 620   #               625  #               630 Leu Ile Ala Ile Leu Ala Leu Ala Val Leu Le#u Leu Ala Ala Gly                 635   #               640  #               645 Leu Ala Ala His Leu Gly Thr Gly Gln Pro Ar#g Lys Gly Val Gly                 650   #               655  #               660 Gly Arg Arg Pro Leu Pro Pro Ala Trp Ala Ph#e Trp Gly Trp Ser                 665   #               670  #               675 Ala Pro Ser Val Arg Val Val Ser Ala Pro Le#u Val Leu Pro Trp                 680   #               685  #               690 Asn Pro Gly Arg Lys Leu Pro Arg Ser Ser Gl#u Gly Glu Thr Leu                 695   #               700  #               705 Leu Pro Pro Leu Ser Gln Asn Ser                 710<210> SEQ ID NO 246 <211> LENGTH: 22 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 246 aacaaggtaa gatgccatcc tg           #                   #                 22 <210> SEQ ID NO 247<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 247 aaacttgtcg atggagacca gctc          #                   #                24 <210> SEQ ID NO 248<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 248aggggctgca aagcctggag agcctctcct tctatgacaa ccagc    #                  #45 <210> SEQ ID NO 249 <211> LENGTH: 3401 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 249gcaagccaag gcgctgtttg agaaggtgaa gaagttccgg acccatgtgg  #              50aggaggggga cattgtgtac cgcctctaca tgcggcagac catcatcaag  #             100gtgatcaagt tcatcctcat catctgctac accgtctact acgtgcacaa  #             150catcaagttc gacgtggact gcaccgtgga cattgagagc ctgacgggct  #             200accgcaccta ccgctgtgcc caccccctgg ccacactctt caagatcctg  #             250gcgtccttct acatcagcct agtcatcttc tacggcctca tctgcatgta  #             300cacactgtgg tggatgctac ggcgctccct caagaagtac tcgtttgagt  #             350cgatccgtga ggagagcagc tacagcgaca tccccgacgt caagaacgac  #             400ttcgccttca tgctgcacct cattgaccaa tacgacccgc tctactccaa  #             450gcgcttcgcc gtcttcctgt cggaggtgag tgagaacaag ctgcggcagc  #             500tgaacctcaa caacgagtgg acgctggaca agctccggca gcggctcacc  #             550aagaacgcgc aggacaagct ggagctgcac ctgttcatgc tcagtggcat  #             600ccctgacact gtgtttgacc tggtggagct ggaggtcctc aagctggagc  #             650tgatccccga cgtgaccatc ccgcccagca ttgcccagct cacgggcctc  #             700aaggagctgt ggctctacca cacagcggcc aagattgaag cgcctgcgct  #             750ggccttcctg cgcgagaacc tgcgggcgct gcacatcaag ttcaccgaca  #             800tcaaggagat cccgctgtgg atctatagcc tgaagacact ggaggagctg  #             850cacctgacgg gcaacctgag cgcggagaac aaccgctaca tcgtcatcga  #             900cgggctgcgg gagctcaaac gcctcaaggt gctgcggctc aagagcaacc  #             950taagcaagct gccacaggtg gtcacagatg tgggcgtgca cctgcagaag  #            1000ctgtccatca acaatgaggg caccaagctc atcgtcctca acagcctcaa  #            1050gaagatggcg aacctgactg agctggagct gatccgctgc gacctggagc  #            1100gcatccccca ctccatcttc agcctccaca acctgcagga gattgacctc  #            1150aaggacaaca acctcaagac catcgaggag atcatcagct tccagcacct  #            1200gcaccgcctc acctgcctta agctgtggta caaccacatc gcctacatcc  #            1250ccatccagat cggcaacctc accaacctgg agcgcctcta cctgaaccgc  #            1300aacaagatcg agaagatccc cacccagctc ttctactgcc gcaagctgcg  #            1350ctacctggac ctcagccaca acaacctgac cttcctccct gccgacatcg  #            1400gcctcctgca gaacctccag aacctagcca tcacggccaa ccggatcgag  #            1450acgctccctc cggagctctt ccagtgccgg aagctgcggg ccctgcacct  #            1500gggcaacaac gtgctgcagt cactgccctc cagggtgggc gagctgacca  #            1550acctgacgca gatcgagctg cggggcaacc ggctggagtg cctgcctgtg  #            1600gagctgggcg agtgcccact gctcaagcgc agcggcttgg tggtggagga  #            1650ggacctgttc aacacactgc cacccgaggt gaaggagcgg ctgtggaggg  #            1700ctgacaagga gcaggcctga gcgaggccgg cccagcacag caagcagcag  #            1750gaccgctgcc cagtcctcag gcccggaggg gcaggcctag cttctcccag  #            1800aactcccgga cagccaggac agcctcgcgg ctgggcagga gcctggggcc  #            1850gcttgtgagt caggccagag cgagaggaca gtatctgtgg ggctggcccc  #            1900ttttctccct ctgagactca cgtcccccag ggcaagtgct tgtggaggag  #            1950agcaagtctc aagagcgcag tatttggata atcagggtct cctccctgga  #            2000ggccagctct gccccagggg ctgagctgcc accagaggtc ctgggaccct  #            2050cactttagtt cttggtattt atttttctcc atctcccacc tccttcatcc  #            2100agataactta tacattccca agaaagttca gcccagatgg aaggtgttca  #            2150gggaaaggtg ggctgccttt tccccttgtc cttatttagc gatgccgccg  #            2200ggcatttaac acccacctgg acttcagcag agtggtccgg ggcgaaccag  #            2250ccatgggacg gtcacccagc agtgccgggc tgggctctgc ggtgcggtcc  #            2300acgggagagc aggcctccag ctggaaaggc caggcctgga gcttgcctct  #            2350tcagtttttg tggcagtttt agttttttgt tttttttttt tttaatcaaa  #            2400aaacaatttt ttttaaaaaa aagctttgaa aatggatggt ttgggtatta  #            2450aaaagaaaaa aaaaacttaa aaaaaaaaag acactaacgg ccagtgagtt  #            2500ggagtctcag ggcagggtgg cagtttccct tgagcaaagc agccagacgt  #            2550tgaactgtgt ttcctttccc tgggcgcagg gtgcagggtg tcttccggat  #            2600ctggtgtgac cttggtccag gagttctatt tgttcctggg gagggaggtt  #            2650tttttgtttg ttttttgggt ttttttggtg tcttgttttc tttctcctcc  #            2700atgtgtcttg gcaggcactc atttctgtgg ctgtcggcca gagggaatgt  #            2750tctggagctg ccaaggaggg aggagactcg ggttggctaa tccccggatg  #            2800aacggtgctc cattcgcacc tcccctcctc gtgcctgccc tgcctctcca  #            2850cgcacagtgt taaggagcca agaggagcca cttcgcccag actttgtttc  #            2900cccacctcct gcggcatggg tgtgtccagt gccaccgctg gcctccgctg  #            2950cttccatcag ccctgtcgcc acctggtcct tcatgaagag cagacactta  #            3000gaggctggtc gggaatgggg aggtcgcccc tgggagggca ggcgttggtt  #            3050ccaagccggt tcccgtccct ggcgcctgga gtgcacacag cccagtcggc  #            3100acctggtggc tggaagccaa cctgctttag atcactcggg tccccacctt  #            3150agaagggtcc ccgccttaga tcaatcacgt ggacactaag gcacgtttta  #            3200gagtctcttg tcttaatgat tatgtccatc cgtctgtccg tccatttgtg  #            3250ttttctgcgt cgtgtcattg gatataatcc tcagaaataa tgcacactag  #            3300cctctgacaa ccatgaagca aaaatccgtt acatgtgggt ctgaacttgt  #            3350agactcggtc acagtatcaa ataaaatcta taacagaaaa aaaaaaaaaa  #            3400 a                   #                  #                   #             3401 <210> SEQ ID NO 250<211> LENGTH: 546 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 250 Met Arg Gln Thr Ile Ile Lys Val Ile Lys Ph#e Ile Leu Ile Ile   1               5  #                 10 #                 15 Cys Tyr Thr Val Tyr Tyr Val His Asn Ile Ly#s Phe Asp Val Asp                  20  #                 25 #                 30 Cys Thr Val Asp Ile Glu Ser Leu Thr Gly Ty#r Arg Thr Tyr Arg                  35  #                 40 #                 45 Cys Ala His Pro Leu Ala Thr Leu Phe Lys Il#e Leu Ala Ser Phe                  50  #                 55 #                 60 Tyr Ile Ser Leu Val Ile Phe Tyr Gly Leu Il#e Cys Met Tyr Thr                  65  #                 70 #                 75 Leu Trp Trp Met Leu Arg Arg Ser Leu Lys Ly#s Tyr Ser Phe Glu                  80  #                 85 #                 90 Ser Ile Arg Glu Glu Ser Ser Tyr Ser Asp Il#e Pro Asp Val Lys                  95  #                100 #                105 Asn Asp Phe Ala Phe Met Leu His Leu Ile As#p Gln Tyr Asp Pro                 110   #               115  #               120 Leu Tyr Ser Lys Arg Phe Ala Val Phe Leu Se#r Glu Val Ser Glu                 125   #               130  #               135 Asn Lys Leu Arg Gln Leu Asn Leu Asn Asn Gl#u Trp Thr Leu Asp                 140   #               145  #               150 Lys Leu Arg Gln Arg Leu Thr Lys Asn Ala Gl#n Asp Lys Leu Glu                 155   #               160  #               165 Leu His Leu Phe Met Leu Ser Gly Ile Pro As#p Thr Val Phe Asp                 170   #               175  #               180 Leu Val Glu Leu Glu Val Leu Lys Leu Glu Le#u Ile Pro Asp Val                 185   #               190  #               195 Thr Ile Pro Pro Ser Ile Ala Gln Leu Thr Gl#y Leu Lys Glu Leu                 200   #               205  #               210 Trp Leu Tyr His Thr Ala Ala Lys Ile Glu Al#a Pro Ala Leu Ala                 215   #               220  #               225 Phe Leu Arg Glu Asn Leu Arg Ala Leu His Il#e Lys Phe Thr Asp                 230   #               235  #               240 Ile Lys Glu Ile Pro Leu Trp Ile Tyr Ser Le#u Lys Thr Leu Glu                 245   #               250  #               255 Glu Leu His Leu Thr Gly Asn Leu Ser Ala Gl#u Asn Asn Arg Tyr                 260   #               265  #               270 Ile Val Ile Asp Gly Leu Arg Glu Leu Lys Ar#g Leu Lys Val Leu                 275   #               280  #               285 Arg Leu Lys Ser Asn Leu Ser Lys Leu Pro Gl#n Val Val Thr Asp                 290   #               295  #               300 Val Gly Val His Leu Gln Lys Leu Ser Ile As#n Asn Glu Gly Thr                 305   #               310  #               315 Lys Leu Ile Val Leu Asn Ser Leu Lys Lys Me#t Ala Asn Leu Thr                 320   #               325  #               330 Glu Leu Glu Leu Ile Arg Cys Asp Leu Glu Ar#g Ile Pro His Ser                 335   #               340  #               345 Ile Phe Ser Leu His Asn Leu Gln Glu Ile As#p Leu Lys Asp Asn                 350   #               355  #               360 Asn Leu Lys Thr Ile Glu Glu Ile Ile Ser Ph#e Gln His Leu His                 365   #               370  #               375 Arg Leu Thr Cys Leu Lys Leu Trp Tyr Asn Hi#s Ile Ala Tyr Ile                 380   #               385  #               390 Pro Ile Gln Ile Gly Asn Leu Thr Asn Leu Gl#u Arg Leu Tyr Leu                 395   #               400  #               405 Asn Arg Asn Lys Ile Glu Lys Ile Pro Thr Gl#n Leu Phe Tyr Cys                 410   #               415  #               420 Arg Lys Leu Arg Tyr Leu Asp Leu Ser His As#n Asn Leu Thr Phe                 425   #               430  #               435 Leu Pro Ala Asp Ile Gly Leu Leu Gln Asn Le#u Gln Asn Leu Ala                 440   #               445  #               450 Ile Thr Ala Asn Arg Ile Glu Thr Leu Pro Pr#o Glu Leu Phe Gln                 455   #               460  #               465 Cys Arg Lys Leu Arg Ala Leu His Leu Gly As#n Asn Val Leu Gln                 470   #               475  #               480 Ser Leu Pro Ser Arg Val Gly Glu Leu Thr As#n Leu Thr Gln Ile                 485   #               490  #               495 Glu Leu Arg Gly Asn Arg Leu Glu Cys Leu Pr#o Val Glu Leu Gly                 500   #               505  #               510 Glu Cys Pro Leu Leu Lys Arg Ser Gly Leu Va#l Val Glu Glu Asp                 515   #               520  #               525 Leu Phe Asn Thr Leu Pro Pro Glu Val Lys Gl#u Arg Leu Trp Arg                 530   #               535  #               540 Ala Asp Lys Glu Gln Ala                 545<210> SEQ ID NO 251 <211> LENGTH: 20 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 251 caacaatgag ggcaccaagc            #                   #                   # 20 <210> SEQ ID NO 252<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 252 gatggctagg ttctggaggt tctg          #                   #                24 <210> SEQ ID NO 253<211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 253caacctgcag gagattgacc tcaaggacaa caacctcaag accatcg   #                47 <210> SEQ ID NO 254 <211> LENGTH: 1650<212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 254gcctgttgct gatgctgccg tgcggtactt gtcatggagc tggcactgcg  #              50gcgctctccc gtcccgcggt ggttgctgct gctgccgctg ctgctgggcc  #             100tgaacgcagg agctgtcatt gactggccca cagaggaggg caaggaagta  #             150tgggattatg tgacggtccg caaggatgcc tacatgttct ggtggctcta  #             200ttatgccacc aactcctgca agaacttctc agaactgccc ctggtcatgt  #             250ggcttcaggg cggtccaggc ggttctagca ctggatttgg aaactttgag  #             300gaaattgggc cccttgacag tgatctcaaa ccacggaaaa ccacctggct  #             350ccaggctgcc agtctcctat ttgtggataa tcccgtgggc actgggttca  #             400gttatgtgaa tggtagtggt gcctatgcca aggacctggc tatggtggct  #             450tcagacatga tggttctcct gaagaccttc ttcagttgcc acaaagaatt  #             500ccagacagtt ccattctaca ttttctcaga gtcctatgga ggaaaaatgg  #             550cagctggcat tggtctagag ctttataagg ccattcagcg agggaccatc  #             600aagtgcaact ttgcgggggt tgccttgggt gattcctgga tctcccctgt  #             650tgattcggtg ctctcctggg gaccttacct gtacagcatg tctcttctcg  #             700aagacaaagg tctggcagag gtgtctaagg ttgcagagca agtactgaat  #             750gccgtaaata aggggctcta cagagaggcc acagagctgt gggggaaagc  #             800agaaatgatc attgaacaga acacagatgg ggtgaacttc tataacatct  #             850taactaaaag cactcccacg tctacaatgg agtcgagtct agaattcaca  #             900cagagccacc tagtttgtct ttgtcagcgc cacgtgagac acctacaacg  #             950agatgcctta agccagctca tgaatggccc catcagaaag aagctcaaaa  #            1000ttattcctga ggatcaatcc tggggaggcc aggctaccaa cgtctttgtg  #            1050aacatggagg aggacttcat gaagccagtc attagcattg tggacgagtt  #            1100gctggaggca gggatcaacg tgacggtgta taatggacag ctggatctca  #            1150tcgtagatac catgggtcag gaggcctggg tgcggaaact gaagtggcca  #            1200gaactgccta aattcagtca gctgaagtgg aaggccctgt acagtgaccc  #            1250taaatctttg gaaacatctg cttttgtcaa gtcctacaag aaccttgctt  #            1300tctactggat tctgaaagct ggtcatatgg ttccttctga ccaaggggac  #            1350atggctctga agatgatgag actggtgact cagcaagaat aggatggatg  #            1400gggctggaga tgagctggtt tggccttggg gcacagagct gagctgaggc  #            1450cgctgaagct gtaggaagcg ccattcttcc ctgtatctaa ctggggctgt  #            1500gatcaagaag gttctgacca gcttctgcag aggataaaat cattgtctct  #            1550ggaggcaatt tggaaattat ttctgcttct taaaaaaacc taagattttt  #            1600taaaaaattg atttgttttg atcaaaataa aggatgataa tagatattaa  #            1650 <210> SEQ ID NO 255 <211> LENGTH: 452 <212> TYPE: PRT<213> ORGANISM: Homo Sapien <400> SEQUENCE: 255Met Glu Leu Ala Leu Arg Arg Ser Pro Val Pr #o Arg Trp Leu Leu  1               5  #                 10  #                 15Leu Leu Pro Leu Leu Leu Gly Leu Asn Ala Gl #y Ala Val Ile Asp                 20  #                 25  #                 30Trp Pro Thr Glu Glu Gly Lys Glu Val Trp As #p Tyr Val Thr Val                 35  #                 40  #                 45Arg Lys Asp Ala Tyr Met Phe Trp Trp Leu Ty #r Tyr Ala Thr Asn                 50  #                 55  #                 60Ser Cys Lys Asn Phe Ser Glu Leu Pro Leu Va #l Met Trp Leu Gln                 65  #                 70  #                 75Gly Gly Pro Gly Gly Ser Ser Thr Gly Phe Gl #y Asn Phe Glu Glu                 80  #                 85  #                 90Ile Gly Pro Leu Asp Ser Asp Leu Lys Pro Ar #g Lys Thr Thr Trp                 95  #                100  #                105Leu Gln Ala Ala Ser Leu Leu Phe Val Asp As #n Pro Val Gly Thr                110   #               115   #               120Gly Phe Ser Tyr Val Asn Gly Ser Gly Ala Ty #r Ala Lys Asp Leu                125   #               130   #               135Ala Met Val Ala Ser Asp Met Met Val Leu Le #u Lys Thr Phe Phe                140   #               145   #               150Ser Cys His Lys Glu Phe Gln Thr Val Pro Ph #e Tyr Ile Phe Ser                155   #               160   #               165Glu Ser Tyr Gly Gly Lys Met Ala Ala Gly Il #e Gly Leu Glu Leu                170   #               175   #               180Tyr Lys Ala Ile Gln Arg Gly Thr Ile Lys Cy #s Asn Phe Ala Gly                185   #               190   #               195Val Ala Leu Gly Asp Ser Trp Ile Ser Pro Va #l Asp Ser Val Leu                200   #               205   #               210Ser Trp Gly Pro Tyr Leu Tyr Ser Met Ser Le #u Leu Glu Asp Lys                215   #               220   #               225Gly Leu Ala Glu Val Ser Lys Val Ala Glu Gl #n Val Leu Asn Ala                230   #               235   #               240Val Asn Lys Gly Leu Tyr Arg Glu Ala Thr Gl #u Leu Trp Gly Lys                245   #               250   #               255Ala Glu Met Ile Ile Glu Gln Asn Thr Asp Gl #y Val Asn Phe Tyr                260   #               265   #               270Asn Ile Leu Thr Lys Ser Thr Pro Thr Ser Th #r Met Glu Ser Ser                275   #               280   #               285Leu Glu Phe Thr Gln Ser His Leu Val Cys Le #u Cys Gln Arg His                290   #               295   #               300Val Arg His Leu Gln Arg Asp Ala Leu Ser Gl #n Leu Met Asn Gly                305   #               310   #               315Pro Ile Arg Lys Lys Leu Lys Ile Ile Pro Gl #u Asp Gln Ser Trp                320   #               325   #               330Gly Gly Gln Ala Thr Asn Val Phe Val Asn Me #t Glu Glu Asp Phe                335   #               340   #               345Met Lys Pro Val Ile Ser Ile Val Asp Glu Le #u Leu Glu Ala Gly                350   #               355   #               360Ile Asn Val Thr Val Tyr Asn Gly Gln Leu As #p Leu Ile Val Asp                365   #               370   #               375Thr Met Gly Gln Glu Ala Trp Val Arg Lys Le #u Lys Trp Pro Glu                380   #               385   #               390Leu Pro Lys Phe Ser Gln Leu Lys Trp Lys Al #a Leu Tyr Ser Asp                395   #               400   #               405Pro Lys Ser Leu Glu Thr Ser Ala Phe Val Ly #s Ser Tyr Lys Asn                410   #               415   #               420Leu Ala Phe Tyr Trp Ile Leu Lys Ala Gly Hi #s Met Val Pro Ser                425   #               430   #               435Asp Gln Gly Asp Met Ala Leu Lys Met Met Ar #g Leu Val Thr Gln                440   #               445   #               450 Gln Glu<210> SEQ ID NO 256 <211> LENGTH: 1100 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 256ggccgcggga gaggaggcca tgggcgcgcg cggggcgctg ctgctggcgc  #              50tgctgctggc tcgggctgga ctcaggaagc cggagtcgca ggaggcggcg  #             100ccgttatcag gaccatgcgg ccgacgggtc atcacgtcgc gcatcgtggg  #             150tggagaggac gccgaactcg ggcgttggcc gtggcagggg agcctgcgcc  #             200tgtgggattc ccacgtatgc ggagtgagcc tgctcagcca ccgctgggca  #             250ctcacggcgg cgcactgctt tgaaacctat agtgacctta gtgatccctc  #             300cgggtggatg gtccagtttg gccagctgac ttccatgcca tccttctgga  #             350gcctgcaggc ctactacacc cgttacttcg tatcgaatat ctatctgagc  #             400cctcgctacc tggggaattc accctatgac attgccttgg tgaagctgtc  #             450tgcacctgtc acctacacta aacacatcca gcccatctgt ctccaggcct  #             500ccacatttga gtttgagaac cggacagact gctgggtgac tggctggggg  #             550tacatcaaag aggatgaggc actgccatct ccccacaccc tccaggaagt  #             600tcaggtcgcc atcataaaca actctatgtg caaccacctc ttcctcaagt  #             650acagtttccg caaggacatc tttggagaca tggtttgtgc tggcaacgcc  #             700caaggcggga aggatgcctg cttcggtgac tcaggtggac ccttggcctg  #             750taacaagaat ggactgtggt atcagattgg agtcgtgagc tggggagtgg  #             800gctgtggtcg gcccaatcgg cccggtgtct acaccaatat cagccaccac  #             850tttgagtgga tccagaagct gatggcccag agtggcatgt cccagccaga  #             900cccctcctgg ccactactct ttttccctct tctctgggct ctcccactcc  #             950tggggccggt ctgagcctac ctgagcccat gcagcctggg gccactgcca  #            1000agtcaggccc tggttctctt ctgtcttgtt tggtaataaa cacattccag  #            1050ttgatgcctt gcagggcatt cttcaaaaaa aaaaaaaaaa aaaaaaaaaa  #            1100 <210> SEQ ID NO 257 <211> LENGTH: 314 <212> TYPE: PRT<213> ORGANISM: Homo Sapien <400> SEQUENCE: 257Met Gly Ala Arg Gly Ala Leu Leu Leu Ala Le #u Leu Leu Ala Arg  1               5  #                 10  #                 15Ala Gly Leu Arg Lys Pro Glu Ser Gln Glu Al #a Ala Pro Leu Ser                 20  #                 25  #                 30Gly Pro Cys Gly Arg Arg Val Ile Thr Ser Ar #g Ile Val Gly Gly                 35  #                 40  #                 45Glu Asp Ala Glu Leu Gly Arg Trp Pro Trp Gl #n Gly Ser Leu Arg                 50  #                 55  #                 60Leu Trp Asp Ser His Val Cys Gly Val Ser Le #u Leu Ser His Arg                 65  #                 70  #                 75Trp Ala Leu Thr Ala Ala His Cys Phe Glu Th #r Tyr Ser Asp Leu                 80  #                 85  #                 90Ser Asp Pro Ser Gly Trp Met Val Gln Phe Gl #y Gln Leu Thr Ser                 95  #                100  #                105Met Pro Ser Phe Trp Ser Leu Gln Ala Tyr Ty #r Thr Arg Tyr Phe                110   #               115   #               120Val Ser Asn Ile Tyr Leu Ser Pro Arg Tyr Le #u Gly Asn Ser Pro                125   #               130   #               135Tyr Asp Ile Ala Leu Val Lys Leu Ser Ala Pr #o Val Thr Tyr Thr                140   #               145   #               150Lys His Ile Gln Pro Ile Cys Leu Gln Ala Se #r Thr Phe Glu Phe                155   #               160   #               165Glu Asn Arg Thr Asp Cys Trp Val Thr Gly Tr #p Gly Tyr Ile Lys                170   #               175   #               180Glu Asp Glu Ala Leu Pro Ser Pro His Thr Le #u Gln Glu Val Gln                185   #               190   #               195Val Ala Ile Ile Asn Asn Ser Met Cys Asn Hi #s Leu Phe Leu Lys                200   #               205   #               210Tyr Ser Phe Arg Lys Asp Ile Phe Gly Asp Me #t Val Cys Ala Gly                215   #               220   #               225Asn Ala Gln Gly Gly Lys Asp Ala Cys Phe Gl #y Asp Ser Gly Gly                230   #               235   #               240Pro Leu Ala Cys Asn Lys Asn Gly Leu Trp Ty #r Gln Ile Gly Val                245   #               250   #               255Val Ser Trp Gly Val Gly Cys Gly Arg Pro As #n Arg Pro Gly Val                260   #               265   #               270Tyr Thr Asn Ile Ser His His Phe Glu Trp Il #e Gln Lys Leu Met                275   #               280   #               285Ala Gln Ser Gly Met Ser Gln Pro Asp Pro Se #r Trp Pro Leu Leu                290   #               295   #               300Phe Phe Pro Leu Leu Trp Ala Leu Pro Leu Le #u Gly Pro Val                305   #               310 <210> SEQ ID NO 258<211> LENGTH: 2427 <212> TYPE: DNA <213> ORGANISM: Homo Sapien<400> SEQUENCE: 258cccacgcgtc cgcggacgcg tgggaagggc agaatgggac tccaagcctg  #              50cctcctaggg ctctttgccc tcatcctctc tggcaaatgc agttacagcc  #             100cggagcccga ccagcggagg acgctgcccc caggctgggt gtccctgggc  #             150cgtgcggacc ctgaggaaga gctgagtctc acctttgccc tgagacagca  #             200gaatgtggaa agactctcgg agctggtgca ggctgtgtcg gatcccagct  #             250ctcctcaata cggaaaatac ctgaccctag agaatgtggc tgatctggtg  #             300aggccatccc cactgaccct ccacacggtg caaaaatggc tcttggcagc  #             350cggagcccag aagtgccatt ctgtgatcac acaggacttt ctgacttgct  #             400ggctgagcat ccgacaagca gagctgctgc tccctggggc tgagtttcat  #             450cactatgtgg gaggacctac ggaaacccat gttgtaaggt ccccacatcc  #             500ctaccagctt ccacaggcct tggcccccca tgtggacttt gtggggggac  #             550tgcaccgttt tcccccaaca tcatccctga ggcaacgtcc tgagccgcag  #             600gtgacaggga ctgtaggcct gcatctgggg gtaaccccct ctgtgatccg  #             650taagcgatac aacttgacct cacaagacgt gggctctggc accagcaata  #             700acagccaagc ctgtgcccag ttcctggagc agtatttcca tgactcagac  #             750ctggctcagt tcatgcgcct cttcggtggc aactttgcac atcaggcatc  #             800agtagcccgt gtggttggac aacagggccg gggccgggcc gggattgagg  #             850ccagtctaga tgtgcagtac ctgatgagtg ctggtgccaa catctccacc  #             900tgggtctaca gtagccctgg ccggcatgag ggacaggagc ccttcctgca  #             950gtggctcatg ctgctcagta atgagtcagc cctgccacat gtgcatactg  #            1000tgagctatgg agatgatgag gactccctca gcagcgccta catccagcgg  #            1050gtcaacactg agctcatgaa ggctgccgct cggggtctca ccctgctctt  #            1100cgcctcaggt gacagtgggg ccgggtgttg gtctgtctct ggaagacacc  #            1150agttccgccc taccttccct gcctccagcc cctatgtcac cacagtggga  #            1200ggcacatcct tccaggaacc tttcctcatc acaaatgaaa ttgttgacta  #            1250tatcagtggt ggtggcttca gcaatgtgtt cccacggcct tcataccagg  #            1300aggaagctgt aacgaagttc ctgagctcta gcccccacct gccaccatcc  #            1350agttacttca atgccagtgg ccgtgcctac ccagatgtgg ctgcactttc  #            1400tgatggctac tgggtggtca gcaacagagt gcccattcca tgggtgtccg  #            1450gaacctcggc ctctactcca gtgtttgggg ggatcctatc cttgatcaat  #            1500gagcacagga tccttagtgg ccgcccccct cttggctttc tcaacccaag  #            1550gctctaccag cagcatgggg caggtctctt tgatgtaacc cgtggctgcc  #            1600atgagtcctg tctggatgaa gaggtagagg gccagggttt ctgctctggt  #            1650cctggctggg atcctgtaac aggctgggga acaccaactt cccagctttg  #            1700ctgaagactc tactcaaccc ctgacccttt cctatcagga gagatggctt  #            1750gtcccctgcc ctgaagctgg cagttcagtc ccttattctg ccctgttgga  #            1800agccctgctg aaccctcaac tattgactgc tgcagacagc ttatctccct  #            1850aaccctgaaa tgctgtgagc ttgacttgac tcccaaccct accatgctcc  #            1900atcatactca ggtctcccta ctcctgcctt agattcctca ataagatgct  #            1950gtaactagca ttttttgaat gcctctccct ccgcatctca tctttctctt  #            2000ttcaatcagg cttttccaaa gggttgtata cagactctgt gcactatttc  #            2050acttgatatt cattccccaa ttcactgcaa ggagacctct actgtcaccg  #            2100tttactcttt cctaccctga catccagaaa caatggcctc cagtgcatac  #            2150ttctcaatct ttgctttatg gcctttccat catagttgcc cactccctct  #            2200ccttacttag cttccaggtc ttaacttctc tgactactct tgtcttcctc  #            2250tctcatcaat ttctgcttct tcatggaatg ctgaccttca ttgctccatt  #            2300tgtagatttt tgctcttctc agtttactca ttgtcccctg gaacaaatca  #            2350ctgacatcta caaccattac catctcacta aataagactt tctatccaat  #            2400 aatgattgat acctcaaatg taaaaaa          #                   #           2427 <210> SEQ ID NO 259<211> LENGTH: 556 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 259 Met Gly Leu Gln Ala Cys Leu Leu Gly Leu Ph#e Ala Leu Ile Leu   1               5  #                 10 #                 15 Ser Gly Lys Cys Ser Tyr Ser Pro Glu Pro As#p Gln Arg Arg Thr                  20  #                 25 #                 30 Leu Pro Pro Gly Trp Val Ser Leu Gly Arg Al#a Asp Pro Glu Glu                  35  #                 40 #                 45 Glu Leu Ser Leu Thr Phe Ala Leu Arg Gln Gl#n Asn Val Glu Arg                  50  #                 55 #                 60 Leu Ser Glu Leu Val Gln Ala Val Ser Asp Pr#o Ser Ser Pro Gln                  65  #                 70 #                 75 Tyr Gly Lys Tyr Leu Thr Leu Glu Asn Val Al#a Asp Leu Val Arg                  80  #                 85 #                 90 Pro Ser Pro Leu Thr Leu His Thr Val Gln Ly#s Trp Leu Leu Ala                  95  #                100 #                105 Ala Gly Ala Gln Lys Cys His Ser Val Ile Th#r Gln Asp Phe Leu                 110   #               115  #               120 Thr Cys Trp Leu Ser Ile Arg Gln Ala Glu Le#u Leu Leu Pro Gly                 125   #               130  #               135 Ala Glu Phe His His Tyr Val Gly Gly Pro Th#r Glu Thr His Val                 140   #               145  #               150 Val Arg Ser Pro His Pro Tyr Gln Leu Pro Gl#n Ala Leu Ala Pro                 155   #               160  #               165 His Val Asp Phe Val Gly Gly Leu His Arg Ph#e Pro Pro Thr Ser                 170   #               175  #               180 Ser Leu Arg Gln Arg Pro Glu Pro Gln Val Th#r Gly Thr Val Gly                 185   #               190  #               195 Leu His Leu Gly Val Thr Pro Ser Val Ile Ar#g Lys Arg Tyr Asn                 200   #               205  #               210 Leu Thr Ser Gln Asp Val Gly Ser Gly Thr Se#r Asn Asn Ser Gln                 215   #               220  #               225 Ala Cys Ala Gln Phe Leu Glu Gln Tyr Phe Hi#s Asp Ser Asp Leu                 230   #               235  #               240 Ala Gln Phe Met Arg Leu Phe Gly Gly Asn Ph#e Ala His Gln Ala                 245   #               250  #               255 Ser Val Ala Arg Val Val Gly Gln Gln Gly Ar#g Gly Arg Ala Gly                 260   #               265  #               270 Ile Glu Ala Ser Leu Asp Val Gln Tyr Leu Me#t Ser Ala Gly Ala                 275   #               280  #               285 Asn Ile Ser Thr Trp Val Tyr Ser Ser Pro Gl#y Arg His Glu Gly                 290   #               295  #               300 Gln Glu Pro Phe Leu Gln Trp Leu Met Leu Le#u Ser Asn Glu Ser                 305   #               310  #               315 Ala Leu Pro His Val His Thr Val Ser Tyr Gl#y Asp Asp Glu Asp                 320   #               325  #               330 Ser Leu Ser Ser Ala Tyr Ile Gln Arg Val As#n Thr Glu Leu Met                 335   #               340  #               345 Lys Ala Ala Ala Arg Gly Leu Thr Leu Leu Ph#e Ala Ser Gly Asp                 350   #               355  #               360 Ser Gly Ala Gly Cys Trp Ser Val Ser Gly Ar#g His Gln Phe Arg                 365   #               370  #               375 Pro Thr Phe Pro Ala Ser Ser Pro Tyr Val Th#r Thr Val Gly Gly                 380   #               385  #               390 Thr Ser Phe Gln Glu Pro Phe Leu Ile Thr As#n Glu Ile Val Asp                 395   #               400  #               405 Tyr Ile Ser Gly Gly Gly Phe Ser Asn Val Ph#e Pro Arg Pro Ser                 410   #               415  #               420 Tyr Gln Glu Glu Ala Val Thr Lys Phe Leu Se#r Ser Ser Pro His                 425   #               430  #               435 Leu Pro Pro Ser Ser Tyr Phe Asn Ala Ser Gl#y Arg Ala Tyr Pro                 440   #               445  #               450 Asp Val Ala Ala Leu Ser Asp Gly Tyr Trp Va#l Val Ser Asn Arg                 455   #               460  #               465 Val Pro Ile Pro Trp Val Ser Gly Thr Ser Al#a Ser Thr Pro Val                 470   #               475  #               480 Phe Gly Gly Ile Leu Ser Leu Ile Asn Glu Hi#s Arg Ile Leu Ser                 485   #               490  #               495 Gly Arg Pro Pro Leu Gly Phe Leu Asn Pro Ar#g Leu Tyr Gln Gln                 500   #               505  #               510 His Gly Ala Gly Leu Phe Asp Val Thr Arg Gl#y Cys His Glu Ser                 515   #               520  #               525 Cys Leu Asp Glu Glu Val Glu Gly Gln Gly Ph#e Cys Ser Gly Pro                 530   #               535  #               540 Gly Trp Asp Pro Val Thr Gly Trp Gly Thr Pr#o Thr Ser Gln Leu                 545   #               550  #               555 Cys <210> SEQ ID NO 260 <211> LENGTH: 1638<212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 260gccgcgcgct ctctcccggc gcccacacct gtctgagcgg cgcagcgagc  #              50cgcggcccgg gcgggctgct cggcgcggaa cagtgctcgg catggcaggg  #             100attccagggc tcctcttcct tctcttcttt ctgctctgtg ctgttgggca  #             150agtgagccct tacagtgccc cctggaaacc cacttggcct gcataccgcc  #             200tccctgtcgt cttgccccag tctaccctca atttagccaa gccagacttt  #             250ggagccgaag ccaaattaga agtatcttct tcatgtggac cccagtgtca  #             300taagggaact ccactgccca cttacgaaga ggccaagcaa tatctgtctt  #             350atgaaacgct ctatgccaat ggcagccgca cagagacgca ggtgggcatc  #             400tacatcctca gcagtagtgg agatggggcc caacaccgag actcagggtc  #             450ttcaggaaag tctcgaagga agcggcagat ttatggctat gacagcaggt  #             500tcagcatttt tgggaaggac ttcctgctca actacccttt ctcaacatca  #             550gtgaagttat ccacgggctg caccggcacc ctggtggcag agaagcatgt  #             600cctcacagct gcccactgca tacacgatgg aaaaacctat gtgaaaggaa  #             650cccagaagct tcgagtgggc ttcctaaagc ccaagtttaa agatggtggt  #             700cgaggggcca acgactccac ttcagccatg cccgagcaga tgaaatttca  #             750gtggatccgg gtgaaacgca cccatgtgcc caagggttgg atcaagggca  #             800atgccaatga catcggcatg gattatgatt atgccctcct ggaactcaaa  #             850aagccccaca agagaaaatt tatgaagatt ggggtgagcc ctcctgctaa  #             900gcagctgcca gggggcagaa ttcacttctc tggttatgac aatgaccgac  #             950caggcaattt ggtgtatcgc ttctgtgacg tcaaagacga gacctatgac  #            1000ttgctctacc agcaatgcga tgcccagcca ggggccagcg ggtctggggt  #            1050ctatgtgagg atgtggaaga gacagcagca gaagtgggag cgaaaaatta  #            1100ttggcatttt ttcagggcac cagtgggtgg acatgaatgg ttccccacag  #            1150gatttcaacg tggctgtcag aatcactcct ctcaaatatg cccagatttg  #            1200ctattggatt aaaggaaact acctggattg tagggagggg tgacacagtg  #            1250ttccctcctg gcagcaatta agggtcttca tgttcttatt ttaggagagg  #            1300ccaaattgtt ttttgtcatt ggcgtgcaca cgtgtgtgtg tgtgtgtgtg  #            1350tgtgtgtaag gtgtcttata atcttttacc tatttcttac aattgcaaga  #            1400tgactggctt tactatttga aaactggttt gtgtatcata tcatatatca  #            1450tttaagcagt ttgaaggcat acttttgcat agaaataaaa aaaatactga  #            1500tttggggcaa tgaggaatat ttgacaatta agttaatctt cacgtttttg  #            1550caaactttga tttttatttc atctgaactt gtttcaaaga tttatattaa  #            1600 atatttggca tacaagagat atgaaaaaaa aaaaaaaa      #                   #   1638 <210> SEQ ID NO 261 <211> LENGTH: 383<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 261Met Ala Gly Ile Pro Gly Leu Leu Phe Leu Le #u Phe Phe Leu Leu  1               5  #                 10  #                 15Cys Ala Val Gly Gln Val Ser Pro Tyr Ser Al #a Pro Trp Lys Pro                 20  #                 25  #                 30Thr Trp Pro Ala Tyr Arg Leu Pro Val Val Le #u Pro Gln Ser Thr                 35  #                 40  #                 45Leu Asn Leu Ala Lys Pro Asp Phe Gly Ala Gl #u Ala Lys Leu Glu                 50  #                 55  #                 60Val Ser Ser Ser Cys Gly Pro Gln Cys His Ly #s Gly Thr Pro Leu                 65  #                 70  #                 75Pro Thr Tyr Glu Glu Ala Lys Gln Tyr Leu Se #r Tyr Glu Thr Leu                 80  #                 85  #                 90Tyr Ala Asn Gly Ser Arg Thr Glu Thr Gln Va #l Gly Ile Tyr Ile                 95  #                100  #                105Leu Ser Ser Ser Gly Asp Gly Ala Gln His Ar #g Asp Ser Gly Ser                110   #               115   #               120Ser Gly Lys Ser Arg Arg Lys Arg Gln Ile Ty #r Gly Tyr Asp Ser                125   #               130   #               135Arg Phe Ser Ile Phe Gly Lys Asp Phe Leu Le #u Asn Tyr Pro Phe                140   #               145   #               150Ser Thr Ser Val Lys Leu Ser Thr Gly Cys Th #r Gly Thr Leu Val                155   #               160   #               165Ala Glu Lys His Val Leu Thr Ala Ala His Cy #s Ile His Asp Gly                170   #               175   #               180Lys Thr Tyr Val Lys Gly Thr Gln Lys Leu Ar #g Val Gly Phe Leu                185   #               190   #               195Lys Pro Lys Phe Lys Asp Gly Gly Arg Gly Al #a Asn Asp Ser Thr                200   #               205   #               210Ser Ala Met Pro Glu Gln Met Lys Phe Gln Tr #p Ile Arg Val Lys                215   #               220   #               225Arg Thr His Val Pro Lys Gly Trp Ile Lys Gl #y Asn Ala Asn Asp                230   #               235   #               240Ile Gly Met Asp Tyr Asp Tyr Ala Leu Leu Gl #u Leu Lys Lys Pro                245   #               250   #               255His Lys Arg Lys Phe Met Lys Ile Gly Val Se #r Pro Pro Ala Lys                260   #               265   #               270Gln Leu Pro Gly Gly Arg Ile His Phe Ser Gl #y Tyr Asp Asn Asp                275   #               280   #               285Arg Pro Gly Asn Leu Val Tyr Arg Phe Cys As #p Val Lys Asp Glu                290   #               295   #               300Thr Tyr Asp Leu Leu Tyr Gln Gln Cys Asp Al #a Gln Pro Gly Ala                305   #               310   #               315Ser Gly Ser Gly Val Tyr Val Arg Met Trp Ly #s Arg Gln Gln Gln                320   #               325   #               330Lys Trp Glu Arg Lys Ile Ile Gly Ile Phe Se #r Gly His Gln Trp                335   #               340   #               345Val Asp Met Asn Gly Ser Pro Gln Asp Phe As #n Val Ala Val Arg                350   #               355   #               360Ile Thr Pro Leu Lys Tyr Ala Gln Ile Cys Ty #r Trp Ile Lys Gly                365   #               370   #               375Asn Tyr Leu Asp Cys Arg Glu Gly                 380 <210> SEQ ID NO 262<211> LENGTH: 1378 <212> TYPE: DNA <213> ORGANISM: Homo Sapien<400> SEQUENCE: 262gcatcgccct gggtctctcg agcctgctgc ctgctccccc gccccaccag  #              50ccatggtggt ttctggagcg cccccagccc tgggtggggg ctgtctcggc  #             100accttcacct ccctgctgct gctggcgtcg acagccatcc tcaatgcggc  #             150caggatacct gttcccccag cctgtgggaa gccccagcag ctgaaccggg  #             200ttgtgggcgg cgaggacagc actgacagcg agtggccctg gatcgtgagc  #             250atccagaaga atgggaccca ccactgcgca ggttctctgc tcaccagccg  #             300ctgggtgatc actgctgccc actgtttcaa ggacaacctg aacaaaccat  #             350acctgttctc tgtgctgctg ggggcctggc agctggggaa ccctggctct  #             400cggtcccaga aggtgggtgt tgcctgggtg gagccccacc ctgtgtattc  #             450ctggaaggaa ggtgcctgtg cagacattgc cctggtgcgt ctcgagcgct  #             500ccatacagtt ctcagagcgg gtcctgccca tctgcctacc tgatgcctct  #             550atccacctcc ctccaaacac ccactgctgg atctcaggct gggggagcat  #             600ccaagatgga gttcccttgc cccaccctca gaccctgcag aagctgaagg  #             650ttcctatcat cgactcggaa gtctgcagcc atctgtactg gcggggagca  #             700ggacagggac ccatcactga ggacatgctg tgtgccggct acttggaggg  #             750ggagcgggat gcttgtctgg gcgactccgg gggccccctc atgtgccagg  #             800tggacggcgc ctggctgctg gccggcatca tcagctgggg cgagggctgt  #             850gccgagcgca acaggcccgg ggtctacatc agcctctctg cgcaccgctc  #             900ctgggtggag aagatcgtgc aaggggtgca gctccgcggg cgcgctcagg  #             950ggggtggggc cctcagggca ccgagccagg gctctggggc cgccgcgcgc  #            1000tcctagggcg cagcgggacg cggggctcgg atctgaaagg cggccagatc  #            1050cacatctgga tctggatctg cggcggcctc gggcggtttc ccccgccgta  #            1100aataggctca tctacctcta cctctggggg cccggacggc tgctgcggaa  #            1150aggaaacccc ctccccgacc cgcccgacgg cctcaggccc ccctccaagg  #            1200catcaggccc cgcccaacgg cctcatgtcc ccgcccccac gacttccggc  #            1250cccgcccccg ggccccagcg cttttgtgta tataaatgtt aatgattttt  #            1300ataggtattt gtaaccctgc ccacatatct tatttattcc tccaatttca  #            1350 ataaattatt tattctccaa aaaaaaaa         #                   #           1378 <210> SEQ ID NO 263<211> LENGTH: 317 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 263 Met Val Val Ser Gly Ala Pro Pro Ala Leu Gl#y Gly Gly Cys Leu   1               5  #                 10 #                 15 Gly Thr Phe Thr Ser Leu Leu Leu Leu Ala Se#r Thr Ala Ile Leu                  20  #                 25 #                 30 Asn Ala Ala Arg Ile Pro Val Pro Pro Ala Cy#s Gly Lys Pro Gln                  35  #                 40 #                 45 Gln Leu Asn Arg Val Val Gly Gly Glu Asp Se#r Thr Asp Ser Glu                  50  #                 55 #                 60 Trp Pro Trp Ile Val Ser Ile Gln Lys Asn Gl#y Thr His His Cys                  65  #                 70 #                 75 Ala Gly Ser Leu Leu Thr Ser Arg Trp Val Il#e Thr Ala Ala His                  80  #                 85 #                 90 Cys Phe Lys Asp Asn Leu Asn Lys Pro Tyr Le#u Phe Ser Val Leu                  95  #                100 #                105 Leu Gly Ala Trp Gln Leu Gly Asn Pro Gly Se#r Arg Ser Gln Lys                 110   #               115  #               120 Val Gly Val Ala Trp Val Glu Pro His Pro Va#l Tyr Ser Trp Lys                 125   #               130  #               135 Glu Gly Ala Cys Ala Asp Ile Ala Leu Val Ar#g Leu Glu Arg Ser                 140   #               145  #               150 Ile Gln Phe Ser Glu Arg Val Leu Pro Ile Cy#s Leu Pro Asp Ala                 155   #               160  #               165 Ser Ile His Leu Pro Pro Asn Thr His Cys Tr#p Ile Ser Gly Trp                 170   #               175  #               180 Gly Ser Ile Gln Asp Gly Val Pro Leu Pro Hi#s Pro Gln Thr Leu                 185   #               190  #               195 Gln Lys Leu Lys Val Pro Ile Ile Asp Ser Gl#u Val Cys Ser His                 200   #               205  #               210 Leu Tyr Trp Arg Gly Ala Gly Gln Gly Pro Il#e Thr Glu Asp Met                 215   #               220  #               225 Leu Cys Ala Gly Tyr Leu Glu Gly Glu Arg As#p Ala Cys Leu Gly                 230   #               235  #               240 Asp Ser Gly Gly Pro Leu Met Cys Gln Val As#p Gly Ala Trp Leu                 245   #               250  #               255 Leu Ala Gly Ile Ile Ser Trp Gly Glu Gly Cy#s Ala Glu Arg Asn                 260   #               265  #               270 Arg Pro Gly Val Tyr Ile Ser Leu Ser Ala Hi#s Arg Ser Trp Val                 275   #               280  #               285 Glu Lys Ile Val Gln Gly Val Gln Leu Arg Gl#y Arg Ala Gln Gly                 290   #               295  #               300 Gly Gly Ala Leu Arg Ala Pro Ser Gln Gly Se#r Gly Ala Ala Ala                 305   #               310  #               315 Arg Ser <210> SEQ ID NO 264 <211> LENGTH: 24<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 264 gtccgcaagg atgcctacat gttc          #                   #                24 <210> SEQ ID NO 265<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 265 gcagaggtgt ctaaggttg             #                   #                   # 19 <210> SEQ ID NO 266<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 266 agctctagac caatgccagc ttcc          #                   #                24 <210> SEQ ID NO 267<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 267gccaccaact cctgcaagaa cttctcagaa ctgcccctgg tcatg    #                  #45 <210> SEQ ID NO 268 <211> LENGTH: 25 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 268 ggggaattca ccctatgaca ttgcc          #                   #               25 <210> SEQ ID NO 269<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 269 gaatgccctg caagcatcaa ctgg          #                   #                24 <210> SEQ ID NO 270<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 270gcacctgtca cctacactaa acacatccag cccatctgtc tccaggcctc  #              50 <210> SEQ ID NO 271 <211> LENGTH: 26 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 271 gcggaagggc agaatgggac tccaag          #                   #              26 <210> SEQ ID NO 272<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 272 cagccctgcc acatgtgc             #                   #                   #  18 <210> SEQ ID NO 273<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 273 tactgggtgg tcagcaac             #                   #                   #  18 <210> SEQ ID NO 274<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 274 ggcgaagagc agggtgagac cccg          #                   #                24 <210> SEQ ID NO 275<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 275gccctcatcc tctctggcaa atgcagttac agcccggagc ccgac    #                  #45 <210> SEQ ID NO 276 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 276 gggcagggat tccagggctc c           #                   #                   #21 <210> SEQ ID NO 277<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 277 ggctatgaca gcaggttc             #                   #                   #  18 <210> SEQ ID NO 278<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 278 tgacaatgac cgaccagg             #                   #                   #  18 <210> SEQ ID NO 279<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 279 gcatcgcatt gctggtagag caag          #                   #                24 <210> SEQ ID NO 280<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 280ttacagtgcc ccctggaaac ccacttggcc tgcataccgc ctccc    #                  #45 <210> SEQ ID NO 281 <211> LENGTH: 34 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 281 cgtctcgagc gctccataca gttcccttgc ccca       #                   #        34 <210> SEQ ID NO 282 <211> LENGTH: 61<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 282tggaggggga gcgggatgct tgtctgggcg actccggggg ccccctcatg  #              50 tgccaggtgg a                #                  #                   #       61 <210> SEQ ID NO 283 <211> LENGTH: 119<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 283ccctcagacc ctgcagaagc tgaaggttcc tatcatcgac tcggaagtct  #              50gcagccatct gtactggcgg ggagcaggac agggacccat cactgaggac  #             100 atgctgtgtg ccggctact              #                  #                   #119 <210> SEQ ID NO 284 <211> LENGTH: 1875<212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 284gacggctggc caccatgcac ggctcctgca gtttcctgat gcttctgctg  #              50ccgctactgc tactgctggt ggccaccaca ggccccgttg gagccctcac  #             100agatgaggag aaacgtttga tggtggagct gcacaacctc taccgggccc  #             150aggtatcccc gacggcctca gacatgctgc acatgagatg ggacgaggag  #             200ctggccgcct tcgccaaggc ctacgcacgg cagtgcgtgt ggggccacaa  #             250caaggagcgc gggcgccgcg gcgagaatct gttcgccatc acagacgagg  #             300gcatggacgt gccgctggcc atggaggagt ggcaccacga gcgtgagcac  #             350tacaacctca gcgccgccac ctgcagccca ggccagatgt gcggccacta  #             400cacgcaggtg gtatgggcca agacagagag gatcggctgt ggttcccact  #             450tctgtgagaa gctccagggt gttgaggaga ccaacatcga attactggtg  #             500tgcaactatg agcctccggg gaacgtgaag gggaaacggc cctaccagga  #             550ggggactccg tgctcccaat gtccctctgg ctaccactgc aagaactccc  #             600tctgtgaacc catcggaagc ccggaagatg ctcaggattt gccttacctg  #             650gtaactgagg ccccatcctt ccgggcgact gaagcatcag actctaggaa  #             700aatgggtact ccttcttccc tagcaacggg gattccggct ttcttggtaa  #             750cagaggtctc aggctccctg gcaaccaagg ctctgcctgc tgtggaaacc  #             800caggccccaa cttccttagc aacgaaagac ccgccctcca tggcaacaga  #             850ggctccacct tgcgtaacaa ctgaggtccc ttccattttg gcagctcaca  #             900gcctgccctc cttggatgag gagccagtta ccttccccaa atcgacccat  #             950gttcctatcc caaaatcagc agacaaagtg acagacaaaa caaaagtgcc  #            1000ctctaggagc ccagagaact ctctggaccc caagatgtcc ctgacagggg  #            1050caagggaact cctaccccat gcccaggagg aggctgaggc tgaggctgag  #            1100ttgcctcctt ccagtgaggt cttggcctca gtttttccag cccaggacaa  #            1150gccaggtgag ctgcaggcca cactggacca cacggggcac acctcctcca  #            1200agtccctgcc caatttcccc aatacctctg ccaccgctaa tgccacgggt  #            1250gggcgtgccc tggctctgca gtcgtccttg ccaggtgcag agggccctga  #            1300caagcctagc gttgtgtcag ggctgaactc gggccctggt catgtgtggg  #            1350gccctctcct gggactactg ctcctgcctc ctctggtgtt ggctggaatc  #            1400ttctgaatgg gataccactc aaagggtgaa gaggtcagct gtcctcctgt  #            1450catcttcccc accctgtccc cagcccctaa acaagatact tcttggttaa  #            1500ggccctccgg aagggaaagg ctacggggca tgtgcctcat cacaccatcc  #            1550atcctggagg cacaaggcct ggctggctgc gagctcagga ggccgcctga  #            1600ggactgcaca ccgggcccac acctctcctg cccctccctc ctgagtcctg  #            1650ggggtgggag gatttgaggg agctcactgc ctacctggcc tggggctgtc  #            1700tgcccacaca gcatgtgcgc tctccctgag tgcctgtgta gctggggatg  #            1750gggattccta ggggcagatg aaggacaagc cccactggag tggggttctt  #            1800tgagtggggg aggcagggac gagggaagga aagtaactcc tgactctcca  #            1850 ataaaaacct gtccaacctg tgaaa          #                   #             1875 <210> SEQ ID NO 285<211> LENGTH: 463 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 285 Met His Gly Ser Cys Ser Phe Leu Met Leu Le#u Leu Pro Leu Leu   1               5  #                 10 #                 15 Leu Leu Leu Val Ala Thr Thr Gly Pro Val Gl#y Ala Leu Thr Asp                  20  #                 25 #                 30 Glu Glu Lys Arg Leu Met Val Glu Leu His As#n Leu Tyr Arg Ala                  35  #                 40 #                 45 Gln Val Ser Pro Thr Ala Ser Asp Met Leu Hi#s Met Arg Trp Asp                  50  #                 55 #                 60 Glu Glu Leu Ala Ala Phe Ala Lys Ala Tyr Al#a Arg Gln Cys Val                  65  #                 70 #                 75 Trp Gly His Asn Lys Glu Arg Gly Arg Arg Gl#y Glu Asn Leu Phe                  80  #                 85 #                 90 Ala Ile Thr Asp Glu Gly Met Asp Val Pro Le#u Ala Met Glu Glu                  95  #                100 #                105 Trp His His Glu Arg Glu His Tyr Asn Leu Se#r Ala Ala Thr Cys                 110   #               115  #               120 Ser Pro Gly Gln Met Cys Gly His Tyr Thr Gl#n Val Val Trp Ala                 125   #               130  #               135 Lys Thr Glu Arg Ile Gly Cys Gly Ser His Ph#e Cys Glu Lys Leu                 140   #               145  #               150 Gln Gly Val Glu Glu Thr Asn Ile Glu Leu Le#u Val Cys Asn Tyr                 155   #               160  #               165 Glu Pro Pro Gly Asn Val Lys Gly Lys Arg Pr#o Tyr Gln Glu Gly                 170   #               175  #               180 Thr Pro Cys Ser Gln Cys Pro Ser Gly Tyr Hi#s Cys Lys Asn Ser                 185   #               190  #               195 Leu Cys Glu Pro Ile Gly Ser Pro Glu Asp Al#a Gln Asp Leu Pro                 200   #               205  #               210 Tyr Leu Val Thr Glu Ala Pro Ser Phe Arg Al#a Thr Glu Ala Ser                 215   #               220  #               225 Asp Ser Arg Lys Met Gly Thr Pro Ser Ser Le#u Ala Thr Gly Ile                 230   #               235  #               240 Pro Ala Phe Leu Val Thr Glu Val Ser Gly Se#r Leu Ala Thr Lys                 245   #               250  #               255 Ala Leu Pro Ala Val Glu Thr Gln Ala Pro Th#r Ser Leu Ala Thr                 260   #               265  #               270 Lys Asp Pro Pro Ser Met Ala Thr Glu Ala Pr#o Pro Cys Val Thr                 275   #               280  #               285 Thr Glu Val Pro Ser Ile Leu Ala Ala His Se#r Leu Pro Ser Leu                 290   #               295  #               300 Asp Glu Glu Pro Val Thr Phe Pro Lys Ser Th#r His Val Pro Ile                 305   #               310  #               315 Pro Lys Ser Ala Asp Lys Val Thr Asp Lys Th#r Lys Val Pro Ser                 320   #               325  #               330 Arg Ser Pro Glu Asn Ser Leu Asp Pro Lys Me#t Ser Leu Thr Gly                 335   #               340  #               345 Ala Arg Glu Leu Leu Pro His Ala Gln Glu Gl#u Ala Glu Ala Glu                 350   #               355  #               360 Ala Glu Leu Pro Pro Ser Ser Glu Val Leu Al#a Ser Val Phe Pro                 365   #               370  #               375 Ala Gln Asp Lys Pro Gly Glu Leu Gln Ala Th#r Leu Asp His Thr                 380   #               385  #               390 Gly His Thr Ser Ser Lys Ser Leu Pro Asn Ph#e Pro Asn Thr Ser                 395   #               400  #               405 Ala Thr Ala Asn Ala Thr Gly Gly Arg Ala Le#u Ala Leu Gln Ser                 410   #               415  #               420 Ser Leu Pro Gly Ala Glu Gly Pro Asp Lys Pr#o Ser Val Val Ser                 425   #               430  #               435 Gly Leu Asn Ser Gly Pro Gly His Val Trp Gl#y Pro Leu Leu Gly                 440   #               445  #               450 Leu Leu Leu Leu Pro Pro Leu Val Leu Ala Gl#y Ile Phe                 455   #               460 <210> SEQ ID NO 286<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 286 tcctgcagtt tcctgatgc             #                   #                   # 19 <210> SEQ ID NO 287<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 287 ctcatattgc acaccagtaa ttcg          #                   #                24 <210> SEQ ID NO 288<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 288atgaggagaa acgtttgatg gtggagctgc acaacctcta ccggg    #                  #45 <210> SEQ ID NO 289 <211> LENGTH: 3662 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 289gtaactgaag tcaggctttt catttgggaa gccccctcaa cagaattcgg  #              50tcattctcca agttatggtg gacgtacttc tgttgttctc cctctgcttg  #             100ctttttcaca ttagcagacc ggacttaagt cacaacagat tatctttcat  #             150caaggcaagt tccatgagcc accttcaaag ccttcgagaa gtgaaactga  #             200acaacaatga attggagacc attccaaatc tgggaccagt ctcggcaaat  #             250attacacttc tctccttggc tggaaacagg attgttgaaa tactccctga  #             300acatctgaaa gagtttcagt cccttgaaac tttggacctt agcagcaaca  #             350atatttcaga gctccaaact gcatttccag ccctacagct caaatatctg  #             400tatctcaaca gcaaccgagt cacatcaatg gaacctgggt attttgacaa  #             450tttggccaac acactccttg tgttaaagct gaacaggaac cgaatctcag  #             500ctatcccacc caagatgttt aaactgcccc aactgcaaca tctcgaattg  #             550aaccgaaaca agattaaaaa tgtagatgga ctgacattcc aaggccttgg  #             600tgctctgaag tctctgaaaa tgcaaagaaa tggagtaacg aaacttatgg  #             650atggagcttt ttgggggctg agcaacatgg aaattttgca gctggaccat  #             700aacaacctaa cagagattac caaaggctgg ctttacggct tgctgatgct  #             750gcaggaactt catctcagcc aaaatgccat caacaggatc agccctgatg  #             800cctgggagtt ctgccagaag ctcagtgagc tggacctaac tttcaatcac  #             850ttatcaaggt tagatgattc aagcttcctt ggcctaagct tactaaatac  #             900actgcacatt gggaacaaca gagtcagcta cattgctgat tgtgccttcc  #             950gggggctttc cagtttaaag actttggatc tgaagaacaa tgaaatttcc  #            1000tggactattg aagacatgaa tggtgctttc tctgggcttg acaaactgag  #            1050gcgactgata ctccaaggaa atcggatccg ttctattact aaaaaagcct  #            1100tcactggttt ggatgcattg gagcatctag acctgagtga caacgcaatc  #            1150atgtctttac aaggcaatgc attttcacaa atgaagaaac tgcaacaatt  #            1200gcatttaaat acatcaagcc ttttgtgcga ttgccagcta aaatggctcc  #            1250cacagtgggt ggcggaaaac aactttcaga gctttgtaaa tgccagttgt  #            1300gcccatcctc agctgctaaa aggaagaagc atttttgctg ttagcccaga  #            1350tggctttgtg tgtgatgatt ttcccaaacc ccagatcacg gttcagccag  #            1400aaacacagtc ggcaataaaa ggttccaatt tgagtttcat ctgctcagct  #            1450gccagcagca gtgattcccc aatgactttt gcttggaaaa aagacaatga  #            1500actactgcat gatgctgaaa tggaaaatta tgcacacctc cgggcccaag  #            1550gtggcgaggt gatggagtat accaccatcc ttcggctgcg cgaggtggaa  #            1600tttgccagtg aggggaaata tcagtgtgtc atctccaatc actttggttc  #            1650atcctactct gtcaaagcca agcttacagt aaatatgctt ccctcattca  #            1700ccaagacccc catggatctc accatccgag ctggggccat ggcacgcttg  #            1750gagtgtgctg ctgtggggca cccagccccc cagatagcct ggcagaagga  #            1800tgggggcaca gacttcccag ctgcacggga gagacgcatg catgtgatgc  #            1850ccgaggatga cgtgttcttt atcgtggatg tgaagataga ggacattggg  #            1900gtatacagct gcacagctca gaacagtgca ggaagtattt cagcaaatgc  #            1950aactctgact gtcctagaaa caccatcatt tttgcggcca ctgttggacc  #            2000gaactgtaac caagggagaa acagccgtcc tacagtgcat tgctggagga  #            2050agccctcccc ctaaactgaa ctggaccaaa gatgatagcc cattggtggt  #            2100aaccgagagg cacttttttg cagcaggcaa tcagcttctg attattgtgg  #            2150actcagatgt cagtgatgct gggaaataca catgtgagat gtctaacacc  #            2200cttggcactg agagaggaaa cgtgcgcctc agtgtgatcc ccactccaac  #            2250ctgcgactcc cctcagatga cagccccatc gttagacgat gacggatggg  #            2300ccactgtggg tgtcgtgatc atagccgtgg tttgctgtgt ggtgggcacg  #            2350tcactcgtgt gggtggtcat catataccac acaaggcgga ggaatgaaga  #            2400ttgcagcatt accaacacag atgagaccaa cttgccagca gatattccta  #            2450gttatttgtc atctcaggga acgttagctg acaggcagga tgggtacgtg  #            2500tcttcagaaa gtggaagcca ccaccagttt gtcacatctt caggtgctgg  #            2550atttttctta ccacaacatg acagtagtgg gacctgccat attgacaata  #            2600gcagtgaagc tgatgtggaa gctgccacag atctgttcct ttgtccgttt  #            2650ttgggatcca caggccctat gtatttgaag ggaaatgtgt atggctcaga  #            2700tccttttgaa acatatcata caggttgcag tcctgaccca agaacagttt  #            2750taatggacca ctatgagccc agttacataa agaaaaagga gtgctaccca  #            2800tgttctcatc cttcagaaga atcctgcgaa cggagcttca gtaatatatc  #            2850gtggccttca catgtgagga agctacttaa cactagttac tctcacaatg  #            2900aaggacctgg aatgaaaaat ctgtgtctaa acaagtcctc tttagatttt  #            2950agtgcaaatc cagagccagc gtcggttgcc tcgagtaatt ctttcatggg  #            3000tacctttgga aaagctctca ggagacctca cctagatgcc tattcaagct  #            3050ttggacagcc atcagattgt cagccaagag ccttttattt gaaagctcat  #            3100tcttccccag acttggactc tgggtcagag gaagatggga aagaaaggac  #            3150agattttcag gaagaaaatc acatttgtac ctttaaacag actttagaaa  #            3200actacaggac tccaaatttt cagtcttatg acttggacac atagactgaa  #            3250tgagaccaaa ggaaaagctt aacatactac ctcaagtgaa cttttattta  #            3300aaagagagag aatcttatgt tttttaaatg gagttatgaa ttttaaaagg  #            3350ataaaaatgc tttatttata cagatgaacc aaaattacaa aaagttatga  #            3400aaatttttat actgggaatg atgctcatat aagaatacct ttttaaacta  #            3450ttttttaact ttgttttatg caaaaaagta tcttacgtaa attaatgata  #            3500taaatcatga ttattttatg tatttttata atgccagatt tctttttatg  #            3550gaaaatgagt tactaaagca ttttaaataa tacctgcctt gtaccatttt  #            3600ttaaatagaa gttacttcat tatattttgc acattatatt taataaaatg  #            3650 tgtcaatttg aa               #                  #                   #     3662 <210> SEQ ID NO 290 <211> LENGTH: 1059<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 290Met Val Asp Val Leu Leu Leu Phe Ser Leu Cy #s Leu Leu Phe His  1               5  #                 10  #                 15Ile Ser Arg Pro Asp Leu Ser His Asn Arg Le #u Ser Phe Ile Lys                 20  #                 25  #                 30Ala Ser Ser Met Ser His Leu Gln Ser Leu Ar #g Glu Val Lys Leu                 35  #                 40  #                 45Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Le #u Gly Pro Val Ser                 50  #                 55  #                 60Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly As #n Arg Ile Val Glu                 65  #                 70  #                 75Ile Leu Pro Glu His Leu Lys Glu Phe Gln Se #r Leu Glu Thr Leu                 80  #                 85  #                 90Asp Leu Ser Ser Asn Asn Ile Ser Glu Leu Gl #n Thr Ala Phe Pro                 95  #                100  #                105Ala Leu Gln Leu Lys Tyr Leu Tyr Leu Asn Se #r Asn Arg Val Thr                110   #               115   #               120Ser Met Glu Pro Gly Tyr Phe Asp Asn Leu Al #a Asn Thr Leu Leu                125   #               130   #               135Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Al #a Ile Pro Pro Lys                140   #               145   #               150Met Phe Lys Leu Pro Gln Leu Gln His Leu Gl #u Leu Asn Arg Asn                155   #               160   #               165Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gl #n Gly Leu Gly Ala                170   #               175   #               180Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Va #l Thr Lys Leu Met                185   #               190   #               195Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Gl #u Ile Leu Gln Leu                200   #               205   #               210Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gl #y Trp Leu Tyr Gly                215   #               220   #               225Leu Leu Met Leu Gln Glu Leu His Leu Ser Gl #n Asn Ala Ile Asn                230   #               235   #               240Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gl #n Lys Leu Ser Glu                245   #               250   #               255Leu Asp Leu Thr Phe Asn His Leu Ser Arg Le #u Asp Asp Ser Ser                260   #               265   #               270Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu Hi #s Ile Gly Asn Asn                275   #               280   #               285Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Ar #g Gly Leu Ser Ser                290   #               295   #               300Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Il #e Ser Trp Thr Ile                305   #               310   #               315Glu Asp Met Asn Gly Ala Phe Ser Gly Leu As #p Lys Leu Arg Arg                320   #               325   #               330Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser Il #e Thr Lys Lys Ala                335   #               340   #               345Phe Thr Gly Leu Asp Ala Leu Glu His Leu As #p Leu Ser Asp Asn                350   #               355   #               360Ala Ile Met Ser Leu Gln Gly Asn Ala Phe Se #r Gln Met Lys Lys                365   #               370   #               375Leu Gln Gln Leu His Leu Asn Thr Ser Ser Le #u Leu Cys Asp Cys                380   #               385   #               390Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Gl #u Asn Asn Phe Gln                395   #               400   #               405Ser Phe Val Asn Ala Ser Cys Ala His Pro Gl #n Leu Leu Lys Gly                410   #               415   #               420Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Ph #e Val Cys Asp Asp                425   #               430   #               435Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Gl #u Thr Gln Ser Ala                440   #               445   #               450Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Se #r Ala Ala Ser Ser                455   #               460   #               465Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Ly #s Asp Asn Glu Leu                470   #               475   #               480Leu His Asp Ala Glu Met Glu Asn Tyr Ala Hi #s Leu Arg Ala Gln                485   #               490   #               495Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Le #u Arg Leu Arg Glu                500   #               505   #               510Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cy #s Val Ile Ser Asn                515   #               520   #               525His Phe Gly Ser Ser Tyr Ser Val Lys Ala Ly #s Leu Thr Val Asn                530   #               535   #               540Met Leu Pro Ser Phe Thr Lys Thr Pro Met As #p Leu Thr Ile Arg                545   #               550   #               555Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Al #a Val Gly His Pro                560   #               565   #               570Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gl #y Thr Asp Phe Pro                575   #               580   #               585Ala Ala Arg Glu Arg Arg Met His Val Met Pr #o Glu Asp Asp Val                590   #               595   #               600Phe Phe Ile Val Asp Val Lys Ile Glu Asp Il #e Gly Val Tyr Ser                605   #               610   #               615Cys Thr Ala Gln Asn Ser Ala Gly Ser Ile Se #r Ala Asn Ala Thr                620   #               625   #               630Leu Thr Val Leu Glu Thr Pro Ser Phe Leu Ar #g Pro Leu Leu Asp                635   #               640   #               645Arg Thr Val Thr Lys Gly Glu Thr Ala Val Le #u Gln Cys Ile Ala                650   #               655   #               660Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Th #r Lys Asp Asp Ser                665   #               670   #               675Pro Leu Val Val Thr Glu Arg His Phe Phe Al #a Ala Gly Asn Gln                680   #               685   #               690Leu Leu Ile Ile Val Asp Ser Asp Val Ser As #p Ala Gly Lys Tyr                695   #               700   #               705Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Gl #u Arg Gly Asn Val                710   #               715   #               720Arg Leu Ser Val Ile Pro Thr Pro Thr Cys As #p Ser Pro Gln Met                725   #               730   #               735Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp Al #a Thr Val Gly Val                740   #               745   #               750Val Ile Ile Ala Val Val Cys Cys Val Val Gl #y Thr Ser Leu Val                755   #               760   #               765Trp Val Val Ile Ile Tyr His Thr Arg Arg Ar #g Asn Glu Asp Cys                770   #               775   #               780Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pr #o Ala Asp Ile Pro                785   #               790   #               795Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala As #p Arg Gln Asp Gly                800   #               805   #               810Tyr Val Ser Ser Glu Ser Gly Ser His His Gl #n Phe Val Thr Ser                815   #               820   #               825Ser Gly Ala Gly Phe Phe Leu Pro Gln His As #p Ser Ser Gly Thr                830   #               835   #               840Cys His Ile Asp Asn Ser Ser Glu Ala Asp Va #l Glu Ala Ala Thr                845   #               850   #               855Asp Leu Phe Leu Cys Pro Phe Leu Gly Ser Th #r Gly Pro Met Tyr                860   #               865   #               870Leu Lys Gly Asn Val Tyr Gly Ser Asp Pro Ph #e Glu Thr Tyr His                875   #               880   #               885Thr Gly Cys Ser Pro Asp Pro Arg Thr Val Le #u Met Asp His Tyr                890   #               895   #               900Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Ty #r Pro Cys Ser His                905   #               910   #               915Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Se #r Asn Ile Ser Trp                920   #               925   #               930Pro Ser His Val Arg Lys Leu Leu Asn Thr Se #r Tyr Ser His Asn                935   #               940   #               945Glu Gly Pro Gly Met Lys Asn Leu Cys Leu As #n Lys Ser Ser Leu                950   #               955   #               960Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Va #l Ala Ser Ser Asn                965   #               970   #               975Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Ar #g Arg Pro His Leu                980   #               985   #               990Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser As #p Cys Gln Pro Arg                995   #              1000    #             1005Ala Phe Tyr Leu Lys Ala His Ser Ser Pro As #p Leu Asp Ser Gly               1010   #              1015    #             1020Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Ph #e Gln Glu Glu Asn               1025   #              1030    #             1035His Ile Cys Thr Phe Lys Gln Thr Leu Glu As #n Tyr Arg Thr Pro               1040   #              1045    #             1050Asn Phe Gln Ser Tyr Asp Leu Asp Thr                1055<210> SEQ ID NO 291 <211> LENGTH: 2906 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 291ggggagagga attgaccatg taaaaggaga cttttttttt tggtggtggt  #              50ggctgttggg tgccttgcaa aaatgaagga tgcaggacgc agctttctcc  #             100tggaaccgaa cgcaatggat aaactgattg tgcaagagag aaggaagaac  #             150gaagcttttt cttgtgagcc ctggatctta acacaaatgt gtatatgtgc  #             200acacagggag cattcaagaa tgaaataaac cagagttaga cccgcggggg  #             250ttggtgtgtt ctgacataaa taaataatct taaagcagct gttcccctcc  #             300ccacccccaa aaaaaaggat gattggaaat gaagaaccga ggattcacaa  #             350agaaaaaagt atgttcattt ttctctataa aggagaaagt gagccaagga  #             400gatatttttg gaatgaaaag tttggggctt ttttagtaaa gtaaagaact  #             450ggtgtggtgg tgttttcctt tctttttgaa tttcccacaa gaggagagga  #             500aattaataat acatctgcaa agaaatttca gagaagaaaa gttgaccgcg  #             550gcagattgag gcattgattg ggggagagaa accagcagag cacagttgga  #             600tttgtgccta tgttgactaa aattgacgga taattgcagt tggatttttc  #             650ttcatcaacc tccttttttt taaattttta ttccttttgg tatcaagatc  #             700atgcgttttc tcttgttctt aaccacctgg atttccatct ggatgttgct  #             750gtgatcagtc tgaaatacaa ctgtttgaat tccagaagga ccaacaccag  #             800ataaattatg aatgttgaac aagatgacct tacatccaca gcagataatg  #             850ataggtccta ggtttaacag ggccctattt gaccccctgc ttgtggtgct  #             900gctggctctt caacttcttg tggtggctgg tctggtgcgg gctcagacct  #             950gcccttctgt gtgctcctgc agcaaccagt tcagcaaggt gatttgtgtt  #            1000cggaaaaacc tgcgtgaggt tccggatggc atctccacca acacacggct  #            1050gctgaacctc catgagaacc aaatccagat catcaaagtg aacagcttca  #            1100agcacttgag gcacttggaa atcctacagt tgagtaggaa ccatatcaga  #            1150accattgaaa ttggggcttt caatggtctg gcgaacctca acactctgga  #            1200actctttgac aatcgtctta ctaccatccc gaatggagct tttgtatact  #            1250tgtctaaact gaaggagctc tggttgcgaa acaaccccat tgaaagcatc  #            1300ccttcttatg cttttaacag aattccttct ttgcgccgac tagacttagg  #            1350ggaattgaaa agactttcat acatctcaga aggtgccttt gaaggtctgt  #            1400ccaacttgag gtatttgaac cttgccatgt gcaaccttcg ggaaatccct  #            1450aacctcacac cgctcataaa actagatgag ctggatcttt ctgggaatca  #            1500tttatctgcc atcaggcctg gctctttcca gggtttgatg caccttcaaa  #            1550aactgtggat gatacagtcc cagattcaag tgattgaacg gaatgccttt  #            1600gacaaccttc agtcactagt ggagatcaac ctggcacaca ataatctaac  #            1650attactgcct catgacctct tcactccctt gcatcatcta gagcggatac  #            1700atttacatca caacccttgg aactgtaact gtgacatact gtggctcagc  #            1750tggtggataa aagacatggc cccctcgaac acagcttgtt gtgcccggtg  #            1800taacactcct cccaatctaa aggggaggta cattggagag ctcgaccaga  #            1850attacttcac atgctatgct ccggtgattg tggagccccc tgcagacctc  #            1900aatgtcactg aaggcatggc agctgagctg aaatgtcggg cctccacatc  #            1950cctgacatct gtatcttgga ttactccaaa tggaacagtc atgacacatg  #            2000gggcgtacaa agtgcggata gctgtgctca gtgatggtac gttaaatttc  #            2050acaaatgtaa ctgtgcaaga tacaggcatg tacacatgta tggtgagtaa  #            2100ttccgttggg aatactactg cttcagccac cctgaatgtt actgcagcaa  #            2150ccactactcc tttctcttac ttttcaaccg tcacagtaga gactatggaa  #            2200ccgtctcagg atgaggcacg gaccacagat aacaatgtgg gtcccactcc  #            2250agtggtcgac tgggagacca ccaatgtgac cacctctctc acaccacaga  #            2300gcacaaggtc gacagagaaa accttcacca tcccagtgac tgatataaac  #            2350agtgggatcc caggaattga tgaggtcatg aagactacca aaatcatcat  #            2400tgggtgtttt gtggccatca cactcatggc tgcagtgatg ctggtcattt  #            2450tctacaagat gaggaagcag caccatcggc aaaaccatca cgccccaaca  #            2500aggactgttg aaattattaa tgtggatgat gagattacgg gagacacacc  #            2550catggaaagc cacctgccca tgcctgctat cgagcatgag cacctaaatc  #            2600actataactc atacaaatct cccttcaacc acacaacaac agttaacaca  #            2650ataaattcaa tacacagttc agtgcatgaa ccgttattga tccgaatgaa  #            2700ctctaaagac aatgtacaag agactcaaat ctaaaacatt tacagagtta  #            2750caaaaaacaa acaatcaaaa aaaaagacag tttattaaaa atgacacaaa  #            2800tgactgggct aaatctactg tttcaaaaaa gtgtctttac aaaaaaacaa  #            2850aaaagaaaag aaatttattt attaaaaatt ctattgtgat ctaaagcaga  #            2900 caaaaa                  #                  #                   #         2906 <210> SEQ ID NO 292 <211> LENGTH: 640<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 292Met Leu Asn Lys Met Thr Leu His Pro Gln Gl #n Ile Met Ile Gly  1               5  #                 10  #                 15Pro Arg Phe Asn Arg Ala Leu Phe Asp Pro Le #u Leu Val Val Leu                 20  #                 25  #                 30Leu Ala Leu Gln Leu Leu Val Val Ala Gly Le #u Val Arg Ala Gln                 35  #                 40  #                 45Thr Cys Pro Ser Val Cys Ser Cys Ser Asn Gl #n Phe Ser Lys Val                 50  #                 55  #                 60Ile Cys Val Arg Lys Asn Leu Arg Glu Val Pr #o Asp Gly Ile Ser                 65  #                 70  #                 75Thr Asn Thr Arg Leu Leu Asn Leu His Glu As #n Gln Ile Gln Ile                 80  #                 85  #                 90Ile Lys Val Asn Ser Phe Lys His Leu Arg Hi #s Leu Glu Ile Leu                 95  #                100  #                105Gln Leu Ser Arg Asn His Ile Arg Thr Ile Gl #u Ile Gly Ala Phe                110   #               115   #               120Asn Gly Leu Ala Asn Leu Asn Thr Leu Glu Le #u Phe Asp Asn Arg                125   #               130   #               135Leu Thr Thr Ile Pro Asn Gly Ala Phe Val Ty #r Leu Ser Lys Leu                140   #               145   #               150Lys Glu Leu Trp Leu Arg Asn Asn Pro Ile Gl #u Ser Ile Pro Ser                155   #               160   #               165Tyr Ala Phe Asn Arg Ile Pro Ser Leu Arg Ar #g Leu Asp Leu Gly                170   #               175   #               180Glu Leu Lys Arg Leu Ser Tyr Ile Ser Glu Gl #y Ala Phe Glu Gly                185   #               190   #               195Leu Ser Asn Leu Arg Tyr Leu Asn Leu Ala Me #t Cys Asn Leu Arg                200   #               205   #               210Glu Ile Pro Asn Leu Thr Pro Leu Ile Lys Le #u Asp Glu Leu Asp                215   #               220   #               225Leu Ser Gly Asn His Leu Ser Ala Ile Arg Pr #o Gly Ser Phe Gln                230   #               235   #               240Gly Leu Met His Leu Gln Lys Leu Trp Met Il #e Gln Ser Gln Ile                245   #               250   #               255Gln Val Ile Glu Arg Asn Ala Phe Asp Asn Le #u Gln Ser Leu Val                260   #               265   #               270Glu Ile Asn Leu Ala His Asn Asn Leu Thr Le #u Leu Pro His Asp                275   #               280   #               285Leu Phe Thr Pro Leu His His Leu Glu Arg Il #e His Leu His His                290   #               295   #               300Asn Pro Trp Asn Cys Asn Cys Asp Ile Leu Tr #p Leu Ser Trp Trp                305   #               310   #               315Ile Lys Asp Met Ala Pro Ser Asn Thr Ala Cy #s Cys Ala Arg Cys                320   #               325   #               330Asn Thr Pro Pro Asn Leu Lys Gly Arg Tyr Il #e Gly Glu Leu Asp                335   #               340   #               345Gln Asn Tyr Phe Thr Cys Tyr Ala Pro Val Il #e Val Glu Pro Pro                350   #               355   #               360Ala Asp Leu Asn Val Thr Glu Gly Met Ala Al #a Glu Leu Lys Cys                365   #               370   #               375Arg Ala Ser Thr Ser Leu Thr Ser Val Ser Tr #p Ile Thr Pro Asn                380   #               385   #               390Gly Thr Val Met Thr His Gly Ala Tyr Lys Va #l Arg Ile Ala Val                395   #               400   #               405Leu Ser Asp Gly Thr Leu Asn Phe Thr Asn Va #l Thr Val Gln Asp                410   #               415   #               420Thr Gly Met Tyr Thr Cys Met Val Ser Asn Se #r Val Gly Asn Thr                425   #               430   #               435Thr Ala Ser Ala Thr Leu Asn Val Thr Ala Al #a Thr Thr Thr Pro                440   #               445   #               450Phe Ser Tyr Phe Ser Thr Val Thr Val Glu Th #r Met Glu Pro Ser                455   #               460   #               465Gln Asp Glu Ala Arg Thr Thr Asp Asn Asn Va #l Gly Pro Thr Pro                470   #               475   #               480Val Val Asp Trp Glu Thr Thr Asn Val Thr Th #r Ser Leu Thr Pro                485   #               490   #               495Gln Ser Thr Arg Ser Thr Glu Lys Thr Phe Th #r Ile Pro Val Thr                500   #               505   #               510Asp Ile Asn Ser Gly Ile Pro Gly Ile Asp Gl #u Val Met Lys Thr                515   #               520   #               525Thr Lys Ile Ile Ile Gly Cys Phe Val Ala Il #e Thr Leu Met Ala                530   #               535   #               540Ala Val Met Leu Val Ile Phe Tyr Lys Met Ar #g Lys Gln His His                545   #               550   #               555Arg Gln Asn His His Ala Pro Thr Arg Thr Va #l Glu Ile Ile Asn                560   #               565   #               570Val Asp Asp Glu Ile Thr Gly Asp Thr Pro Me #t Glu Ser His Leu                575   #               580   #               585Pro Met Pro Ala Ile Glu His Glu His Leu As #n His Tyr Asn Ser                590   #               595   #               600Tyr Lys Ser Pro Phe Asn His Thr Thr Thr Va #l Asn Thr Ile Asn                605   #               610   #               615Ser Ile His Ser Ser Val His Glu Pro Leu Le #u Ile Arg Met Asn                620   #               625   #               630Ser Lys Asp Asn Val Gln Glu Thr Gln Ile                 635  #               640 <210> SEQ ID NO 293 <211> LENGTH: 4053<212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 293agccgacgct gctcaagctg caactctgtt gcagttggca gttcttttcg  #              50gtttccctcc tgctgtttgg gggcatgaaa gggcttcgcc gccgggagta  #             100aaagaaggaa ttgaccgggc agcgcgaggg aggagcgcgc acgcgaccgc  #             150gagggcgggc gtgcaccctc ggctggaagt ttgtgccggg ccccgagcgc  #             200gcgccggctg ggagcttcgg gtagagacct aggccgctgg accgcgatga  #             250gcgcgccgag cctccgtgcg cgcgccgcgg ggttggggct gctgctgtgc  #             300gcggtgctgg ggcgcgctgg ccggtccgac agcggcggtc gcggggaact  #             350cgggcagccc tctggggtag ccgccgagcg cccatgcccc actacctgcc  #             400gctgcctcgg ggacctgctg gactgcagtc gtaagcggct agcgcgtctt  #             450cccgagccac tcccgtcctg ggtcgctcgg ctggacttaa gtcacaacag  #             500attatctttc atcaaggcaa gttccatgag ccaccttcaa agccttcgag  #             550aagtgaaact gaacaacaat gaattggaga ccattccaaa tctgggacca  #             600gtctcggcaa atattacact tctctccttg gctggaaaca ggattgttga  #             650aatactccct gaacatctga aagagtttca gtcccttgaa actttggacc  #             700ttagcagcaa caatatttca gagctccaaa ctgcatttcc agccctacag  #             750ctcaaatatc tgtatctcaa cagcaaccga gtcacatcaa tggaacctgg  #             800gtattttgac aatttggcca acacactcct tgtgttaaag ctgaacagga  #             850accgaatctc agctatccca cccaagatgt ttaaactgcc ccaactgcaa  #             900catctcgaat tgaaccgaaa caagattaaa aatgtagatg gactgacatt  #             950ccaaggcctt ggtgctctga agtctctgaa aatgcaaaga aatggagtaa  #            1000cgaaacttat ggatggagct ttttgggggc tgagcaacat ggaaattttg  #            1050cagctggacc ataacaacct aacagagatt accaaaggct ggctttacgg  #            1100cttgctgatg ctgcaggaac ttcatctcag ccaaaatgcc atcaacagga  #            1150tcagccctga tgcctgggag ttctgccaga agctcagtga gctggaccta  #            1200actttcaatc acttatcaag gttagatgat tcaagcttcc ttggcctaag  #            1250cttactaaat acactgcaca ttgggaacaa cagagtcagc tacattgctg  #            1300attgtgcctt ccgggggctt tccagtttaa agactttgga tctgaagaac  #            1350aatgaaattt cctggactat tgaagacatg aatggtgctt tctctgggct  #            1400tgacaaactg aggcgactga tactccaagg aaatcggatc cgttctatta  #            1450ctaaaaaagc cttcactggt ttggatgcat tggagcatct agacctgagt  #            1500gacaacgcaa tcatgtcttt acaaggcaat gcattttcac aaatgaagaa  #            1550actgcaacaa ttgcatttaa atacatcaag ccttttgtgc gattgccagc  #            1600taaaatggct cccacagtgg gtggcggaaa acaactttca gagctttgta  #            1650aatgccagtt gtgcccatcc tcagctgcta aaaggaagaa gcatttttgc  #            1700tgttagccca gatggctttg tgtgtgatga ttttcccaaa ccccagatca  #            1750cggttcagcc agaaacacag tcggcaataa aaggttccaa tttgagtttc  #            1800atctgctcag ctgccagcag cagtgattcc ccaatgactt ttgcttggaa  #            1850aaaagacaat gaactactgc atgatgctga aatggaaaat tatgcacacc  #            1900tccgggccca aggtggcgag gtgatggagt ataccaccat ccttcggctg  #            1950cgcgaggtgg aatttgccag tgaggggaaa tatcagtgtg tcatctccaa  #            2000tcactttggt tcatcctact ctgtcaaagc caagcttaca gtaaatatgc  #            2050ttccctcatt caccaagacc cccatggatc tcaccatccg agctggggcc  #            2100atggcacgct tggagtgtgc tgctgtgggg cacccagccc cccagatagc  #            2150ctggcagaag gatgggggca cagacttccc agctgcacgg gagagacgca  #            2200tgcatgtgat gcccgaggat gacgtgttct ttatcgtgga tgtgaagata  #            2250gaggacattg gggtatacag ctgcacagct cagaacagtg caggaagtat  #            2300ttcagcaaat gcaactctga ctgtcctaga aacaccatca tttttgcggc  #            2350cactgttgga ccgaactgta accaagggag aaacagccgt cctacagtgc  #            2400attgctggag gaagccctcc ccctaaactg aactggacca aagatgatag  #            2450cccattggtg gtaaccgaga ggcacttttt tgcagcaggc aatcagcttc  #            2500tgattattgt ggactcagat gtcagtgatg ctgggaaata cacatgtgag  #            2550atgtctaaca cccttggcac tgagagagga aacgtgcgcc tcagtgtgat  #            2600ccccactcca acctgcgact cccctcagat gacagcccca tcgttagacg  #            2650atgacggatg ggccactgtg ggtgtcgtga tcatagccgt ggtttgctgt  #            2700gtggtgggca cgtcactcgt gtgggtggtc atcatatacc acacaaggcg  #            2750gaggaatgaa gattgcagca ttaccaacac agatgagacc aacttgccag  #            2800cagatattcc tagttatttg tcatctcagg gaacgttagc tgacaggcag  #            2850gatgggtacg tgtcttcaga aagtggaagc caccaccagt ttgtcacatc  #            2900ttcaggtgct ggatttttct taccacaaca tgacagtagt gggacctgcc  #            2950atattgacaa tagcagtgaa gctgatgtgg aagctgccac agatctgttc  #            3000ctttgtccgt ttttgggatc cacaggccct atgtatttga agggaaatgt  #            3050gtatggctca gatccttttg aaacatatca tacaggttgc agtcctgacc  #            3100caagaacagt tttaatggac cactatgagc ccagttacat aaagaaaaag  #            3150gagtgctacc catgttctca tccttcagaa gaatcctgcg aacggagctt  #            3200cagtaatata tcgtggcctt cacatgtgag gaagctactt aacactagtt  #            3250actctcacaa tgaaggacct ggaatgaaaa atctgtgtct aaacaagtcc  #            3300tctttagatt ttagtgcaaa tccagagcca gcgtcggttg cctcgagtaa  #            3350ttctttcatg ggtacctttg gaaaagctct caggagacct cacctagatg  #            3400cctattcaag ctttggacag ccatcagatt gtcagccaag agccttttat  #            3450ttgaaagctc attcttcccc agacttggac tctgggtcag aggaagatgg  #            3500gaaagaaagg acagattttc aggaagaaaa tcacatttgt acctttaaac  #            3550agactttaga aaactacagg actccaaatt ttcagtctta tgacttggac  #            3600acatagactg aatgagacca aaggaaaagc ttaacatact acctcaagtg  #            3650aacttttatt taaaagagag agaatcttat gttttttaaa tggagttatg  #            3700aattttaaaa ggataaaaat gctttattta tacagatgaa ccaaaattac  #            3750aaaaagttat gaaaattttt atactgggaa tgatgctcat ataagaatac  #            3800ctttttaaac tattttttaa ctttgtttta tgcaaaaaag tatcttacgt  #            3850aaattaatga tataaatcat gattatttta tgtattttta taatgccaga  #            3900tttcttttta tggaaaatga gttactaaag cattttaaat aatacctgcc  #            3950ttgtaccatt ttttaaatag aagttacttc attatatttt gcacattata  #            4000tttaataaaa tgtgtcaatt tgaaaaaaaa aaaaaaaaaa aaaaaaaaaa  #            4050 aaa                   #                  #                   #           4053 <210> SEQ ID NO 294<211> LENGTH: 1119 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 294 Met Ser Ala Pro Ser Leu Arg Ala Arg Ala Al#a Gly Leu Gly Leu   1               5  #                 10 #                 15 Leu Leu Cys Ala Val Leu Gly Arg Ala Gly Ar#g Ser Asp Ser Gly                  20  #                 25 #                 30 Gly Arg Gly Glu Leu Gly Gln Pro Ser Gly Va#l Ala Ala Glu Arg                  35  #                 40 #                 45 Pro Cys Pro Thr Thr Cys Arg Cys Leu Gly As#p Leu Leu Asp Cys                  50  #                 55 #                 60 Ser Arg Lys Arg Leu Ala Arg Leu Pro Glu Pr#o Leu Pro Ser Trp                  65  #                 70 #                 75 Val Ala Arg Leu Asp Leu Ser His Asn Arg Le#u Ser Phe Ile Lys                  80  #                 85 #                 90 Ala Ser Ser Met Ser His Leu Gln Ser Leu Ar#g Glu Val Lys Leu                  95  #                100 #                105 Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Le#u Gly Pro Val Ser                 110   #               115  #               120 Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly As#n Arg Ile Val Glu                 125   #               130  #               135 Ile Leu Pro Glu His Leu Lys Glu Phe Gln Se#r Leu Glu Thr Leu                 140   #               145  #               150 Asp Leu Ser Ser Asn Asn Ile Ser Glu Leu Gl#n Thr Ala Phe Pro                 155   #               160  #               165 Ala Leu Gln Leu Lys Tyr Leu Tyr Leu Asn Se#r Asn Arg Val Thr                 170   #               175  #               180 Ser Met Glu Pro Gly Tyr Phe Asp Asn Leu Al#a Asn Thr Leu Leu                 185   #               190  #               195 Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Al#a Ile Pro Pro Lys                 200   #               205  #               210 Met Phe Lys Leu Pro Gln Leu Gln His Leu Gl#u Leu Asn Arg Asn                 215   #               220  #               225 Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gl#n Gly Leu Gly Ala                 230   #               235  #               240 Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Va#l Thr Lys Leu Met                 245   #               250  #               255 Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Gl#u Ile Leu Gln Leu                 260   #               265  #               270 Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gl#y Trp Leu Tyr Gly                 275   #               280  #               285 Leu Leu Met Leu Gln Glu Leu His Leu Ser Gl#n Asn Ala Ile Asn                 290   #               295  #               300 Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gl#n Lys Leu Ser Glu                 305   #               310  #               315 Leu Asp Leu Thr Phe Asn His Leu Ser Arg Le#u Asp Asp Ser Ser                 320   #               325  #               330 Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu Hi#s Ile Gly Asn Asn                 335   #               340  #               345 Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Ar#g Gly Leu Ser Ser                 350   #               355  #               360 Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Il#e Ser Trp Thr Ile                 365   #               370  #               375 Glu Asp Met Asn Gly Ala Phe Ser Gly Leu As#p Lys Leu Arg Arg                 380   #               385  #               390 Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser Il#e Thr Lys Lys Ala                 395   #               400  #               405 Phe Thr Gly Leu Asp Ala Leu Glu His Leu As#p Leu Ser Asp Asn                 410   #               415  #               420 Ala Ile Met Ser Leu Gln Gly Asn Ala Phe Se#r Gln Met Lys Lys                 425   #               430  #               435 Leu Gln Gln Leu His Leu Asn Thr Ser Ser Le#u Leu Cys Asp Cys                 440   #               445  #               450 Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Gl#u Asn Asn Phe Gln                 455   #               460  #               465 Ser Phe Val Asn Ala Ser Cys Ala His Pro Gl#n Leu Leu Lys Gly                 470   #               475  #               480 Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Ph#e Val Cys Asp Asp                 485   #               490  #               495 Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Gl#u Thr Gln Ser Ala                 500   #               505  #               510 Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Se#r Ala Ala Ser Ser                 515   #               520  #               525 Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Ly#s Asp Asn Glu Leu                 530   #               535  #               540 Leu His Asp Ala Glu Met Glu Asn Tyr Ala Hi#s Leu Arg Ala Gln                 545   #               550  #               555 Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Le#u Arg Leu Arg Glu                 560   #               565  #               570 Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cy#s Val Ile Ser Asn                 575   #               580  #               585 His Phe Gly Ser Ser Tyr Ser Val Lys Ala Ly#s Leu Thr Val Asn                 590   #               595  #               600 Met Leu Pro Ser Phe Thr Lys Thr Pro Met As#p Leu Thr Ile Arg                 605   #               610  #               615 Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Al#a Val Gly His Pro                 620   #               625  #               630 Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gl#y Thr Asp Phe Pro                 635   #               640  #               645 Ala Ala Arg Glu Arg Arg Met His Val Met Pr#o Glu Asp Asp Val                 650   #               655  #               660 Phe Phe Ile Val Asp Val Lys Ile Glu Asp Il#e Gly Val Tyr Ser                 665   #               670  #               675 Cys Thr Ala Gln Asn Ser Ala Gly Ser Ile Se#r Ala Asn Ala Thr                 680   #               685  #               690 Leu Thr Val Leu Glu Thr Pro Ser Phe Leu Ar#g Pro Leu Leu Asp                 695   #               700  #               705 Arg Thr Val Thr Lys Gly Glu Thr Ala Val Le#u Gln Cys Ile Ala                 710   #               715  #               720 Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Th#r Lys Asp Asp Ser                 725   #               730  #               735 Pro Leu Val Val Thr Glu Arg His Phe Phe Al#a Ala Gly Asn Gln                 740   #               745  #               750 Leu Leu Ile Ile Val Asp Ser Asp Val Ser As#p Ala Gly Lys Tyr                 755   #               760  #               765 Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Gl#u Arg Gly Asn Val                 770   #               775  #               780 Arg Leu Ser Val Ile Pro Thr Pro Thr Cys As#p Ser Pro Gln Met                 785   #               790  #               795 Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp Al#a Thr Val Gly Val                 800   #               805  #               810 Val Ile Ile Ala Val Val Cys Cys Val Val Gl#y Thr Ser Leu Val                 815   #               820  #               825 Trp Val Val Ile Ile Tyr His Thr Arg Arg Ar#g Asn Glu Asp Cys                 830   #               835  #               840 Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pr#o Ala Asp Ile Pro                 845   #               850  #               855 Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala As#p Arg Gln Asp Gly                 860   #               865  #               870 Tyr Val Ser Ser Glu Ser Gly Ser His His Gl#n Phe Val Thr Ser                 875   #               880  #               885 Ser Gly Ala Gly Phe Phe Leu Pro Gln His As#p Ser Ser Gly Thr                 890   #               895  #               900 Cys His Ile Asp Asn Ser Ser Glu Ala Asp Va#l Glu Ala Ala Thr                 905   #               910  #               915 Asp Leu Phe Leu Cys Pro Phe Leu Gly Ser Th#r Gly Pro Met Tyr                 920   #               925  #               930 Leu Lys Gly Asn Val Tyr Gly Ser Asp Pro Ph#e Glu Thr Tyr His                 935   #               940  #               945 Thr Gly Cys Ser Pro Asp Pro Arg Thr Val Le#u Met Asp His Tyr                 950   #               955  #               960 Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Ty#r Pro Cys Ser His                 965   #               970  #               975 Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Se#r Asn Ile Ser Trp                 980   #               985  #               990 Pro Ser His Val Arg Lys Leu Leu Asn Thr Se#r Tyr Ser His Asn                 995   #              1000   #             1005 Glu Gly Pro Gly Met Lys Asn Leu Cys Leu As#n Lys Ser Ser Leu                1010   #              1015   #             1020 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Va#l Ala Ser Ser Asn                1025   #              1030   #             1035 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Ar#g Arg Pro His Leu                1040   #              1045   #             1050 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser As#p Cys Gln Pro Arg                1055   #              1060   #             1065 Ala Phe Tyr Leu Lys Ala His Ser Ser Pro As#p Leu Asp Ser Gly                1070   #              1075   #             1080 Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Ph#e Gln Glu Glu Asn                1085   #              1090   #             1095 His Ile Cys Thr Phe Lys Gln Thr Leu Glu As#n Tyr Arg Thr Pro                1100   #              1105   #             1110 Asn Phe Gln Ser Tyr Asp Leu Asp Thr               1115 <210> SEQ ID NO 295 <211> LENGTH: 18 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 295 ggaaccgaat ctcagcta              #                  #                   #  18 <210> SEQ ID NO 296 <211> LENGTH: 19<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 296 cctaaactga actggacca             #                   #                   # 19 <210> SEQ ID NO 297<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 297 ggctggagac actgaacct             #                   #                   # 19 <210> SEQ ID NO 298<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 298 acagctgcac agctcagaac agtg          #                   #                24 <210> SEQ ID NO 299<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 299 cattcccagt ataaaaattt tc           #                   #                 22 <210> SEQ ID NO 300<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 300 gggtcttggt gaatgagg             #                   #                   #  18 <210> SEQ ID NO 301<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 301 gtgcctctcg gttaccacca atgg          #                   #                24 <210> SEQ ID NO 302<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 302gcggccactg ttggaccgaa ctgtaaccaa gggagaaaca gccgtcctac  #              50 <210> SEQ ID NO 303 <211> LENGTH: 28 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 303 gcctttgaca accttcagtc actagtgg         #                   #             28 <210> SEQ ID NO 304<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 304 ccccatgtgt ccatgactgt tccc          #                   #                24 <210> SEQ ID NO 305<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 305tactgcctca tgacctcttc actcccttgc atcatcttag agcgg    #                  #45 <210> SEQ ID NO 306 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 306 actccaagga aatcggatcc gttc          #                   #                24 <210> SEQ ID NO 307<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 307 ttagcagctg aggatgggca caac          #                   #                24 <210> SEQ ID NO 308<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 308 actccaagga aatcggatcc gttc          #                   #                24 <210> SEQ ID NO 309<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 309gccttcactg gtttggatgc attggagcat ctagacctga gtgacaacgc  #              50 <210> SEQ ID NO 310 <211> LENGTH: 3296 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 310caaaacttgc gtcgcggaga gcgcccagct tgacttgaat ggaaggagcc  #              50cgagcccgcg gagcgcagct gagactgggg gagcgcgttc ggcctgtggg  #             100gcgccgctcg gcgccggggc gcagcaggga aggggaagct gtggtctgcc  #             150ctgctccacg aggcgccact ggtgtgaacc gggagagccc ctgggtggtc  #             200ccgtccccta tccctccttt atatagaaac cttccacact gggaaggcag  #             250cggcgaggca ggagggctca tggtgagcaa ggaggccggc tgatctgcag  #             300gcgcacagca ttccgagttt acagattttt acagatacca aatggaaggc  #             350gaggaggcag aacagcctgc ctggttccat cagccctggc gcccaggcgc  #             400atctgactcg gcaccccctg caggcaccat ggcccagagc cgggtgctgc  #             450tgctcctgct gctgctgccg ccacagctgc acctgggacc tgtgcttgcc  #             500gtgagggccc caggatttgg ccgaagtggc ggccacagcc tgagccccga  #             550agagaacgaa tttgcggagg aggagccggt gctggtactg agccctgagg  #             600agcccgggcc tggcccagcc gcggtcagct gcccccgaga ctgtgcctgt  #             650tcccaggagg gcgtcgtgga ctgtggcggt attgacctgc gtgagttccc  #             700gggggacctg cctgagcaca ccaaccacct atctctgcag aacaaccagc  #             750tggaaaagat ctaccctgag gagctctccc ggctgcaccg gctggagaca  #             800ctgaacctgc aaaacaaccg cctgacttcc cgagggctcc cagagaaggc  #             850gtttgagcat ctgaccaacc tcaattacct gtacttggcc aataacaagc  #             900tgaccttggc accccgcttc ctgccaaacg ccctgatcag tgtggacttt  #             950gctgccaact atctcaccaa gatctatggg ctcacctttg gccagaagcc  #            1000aaacttgagg tctgtgtacc tgcacaacaa caagctggca gacgccgggc  #            1050tgccggacaa catgttcaac ggctccagca acgtcgaggt cctcatcctg  #            1100tccagcaact tcctgcgcca cgtgcccaag cacctgccgc ctgccctgta  #            1150caagctgcac ctcaagaaca acaagctgga gaagatcccc ccgggggcct  #            1200tcagcgagct gagcagcctg cgcgagctat acctgcagaa caactacctg  #            1250actgacgagg gcctggacaa cgagaccttc tggaagctct ccagcctgga  #            1300gtacctggat ctgtccagca acaacctgtc tcgggtccca gctgggctgc  #            1350cgcgcagcct ggtgctgctg cacttggaga agaacgccat ccggagcgtg  #            1400gacgcgaatg tgctgacccc catccgcagc ctggagtacc tgctgctgca  #            1450cagcaaccag ctgcgggagc agggcatcca cccactggcc ttccagggcc  #            1500tcaagcggtt gcacacggtg cacctgtaca acaacgcgct ggagcgcgtg  #            1550cccagtggcc tgcctcgccg cgtgcgcacc ctcatgatcc tgcacaacca  #            1600gatcacaggc attggccgcg aagactttgc caccacctac ttcctggagg  #            1650agctcaacct cagctacaac cgcatcacca gcccacaggt gcaccgcgac  #            1700gccttccgca agctgcgcct gctgcgctcg ctggacctgt cgggcaaccg  #            1750gctgcacacg ctgccacctg ggctgcctcg aaatgtccat gtgctgaagg  #            1800tcaagcgcaa tgagctggct gccttggcac gaggggcgct ggcgggcatg  #            1850gctcagctgc gtgagctgta cctcaccagc aaccgactgc gcagccgagc  #            1900cctgggcccc cgtgcctggg tggacctcgc ccatctgcag ctgctggaca  #            1950tcgccgggaa tcagctcaca gagatccccg aggggctccc cgagtcactt  #            2000gagtacctgt acctgcagaa caacaagatt agtgcggtgc ccgccaatgc  #            2050cttcgactcc acgcccaacc tcaaggggat ctttctcagg tttaacaagc  #            2100tggctgtggg ctccgtggtg gacagtgcct tccggaggct gaagcacctg  #            2150caggtcttgg acattgaagg caacttagag tttggtgaca tttccaagga  #            2200ccgtggccgc ttggggaagg aaaaggagga ggaggaagag gaggaggagg  #            2250aggaagagga aacaagatag tgacaaggtg atgcagatgt gacctaggat  #            2300gatggaccgc cggactcttt tctgcagcac acgcctgtgt gctgtgagcc  #            2350ccccactctg ccgtgctcac acagacacac ccagctgcac acatgaggca  #            2400tcccacatga cacgggctga cacagtctca tatccccacc ccttcccacg  #            2450gcgtgtccca cggccagaca catgcacaca catcacaccc tcaaacaccc  #            2500agctcagcca cacacaacta ccctccaaac caccacagtc tctgtcacac  #            2550ccccactacc gctgccacgc cctctgaatc atgcagggaa gggtctgccc  #            2600ctgccctggc acacacaggc acccattccc tccccctgct gacatgtgta  #            2650tgcgtatgca tacacaccac acacacacac atgcacaagt catgtgcgaa  #            2700cagccctcca aagcctatgc cacagacagc tcttgcccca gccagaatca  #            2750gccatagcag ctcgccgtct gccctgtcca tctgtccgtc cgttccctgg  #            2800agaagacaca agggtatcca tgctctgtgg ccaggtgcct gccaccctct  #            2850ggaactcaca aaagctggct tttattcctt tcccatccta tggggacagg  #            2900agccttcagg actgctggcc tggcctggcc caccctgctc ctccaggtgc  #            2950tgggcagtca ctctgctaag agtccctccc tgccacgccc tggcaggaca  #            3000caggcacttt tccaatgggc aagcccagtg gaggcaggat gggagagccc  #            3050cctgggtgct gctggggcct tggggcagga gtgaagcaga ggtgatgggg  #            3100ctgggctgag ccagggagga aggacccagc tgcacctagg agacaccttt  #            3150gttcttcagg cctgtggggg aagttccggg tgcctttatt ttttattctt  #            3200ttctaaggaa aaaaatgata aaaatctcaa agctgatttt tcttgttata  #            3250 gaaaaactaa tataaaagca ttatccctat ccctgcaaaa aaaaaa   #               3296 <210> SEQ ID NO 311 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 311 gcattggccg cgagactttg cc           #                   #                 22 <210> SEQ ID NO 312<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 312 gcggccacgg tccttggaaa tg           #                   #                 22 <210> SEQ ID NO 313<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 313tggaggagct caacctcagc tacaaccgca tcaccagccc acagg    #                  #45 <210> SEQ ID NO 314 <211> LENGTH: 3003 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 314gggagggggc tccgggcgcc gcgcagcaga cctgctccgg ccgcgcgcct  #              50cgccgctgtc ctccgggagc ggcagcagta gcccgggcgg cgagggctgg  #             100gggttcctcg agactctcag aggggcgcct cccatcggcg cccaccaccc  #             150caacctgttc ctcgcgcgcc actgcgctgc gccccaggac ccgctgccca  #             200acatggattt tctcctggcg ctggtgctgg tatcctcgct ctacctgcag  #             250gcggccgccg agttcgacgg gaggtggccc aggcaaatag tgtcatcgat  #             300tggcctatgt cgttatggtg ggaggattga ctgctgctgg ggctgggctc  #             350gccagtcttg gggacagtgt cagcctgtgt gccaaccacg atgcaaacat  #             400ggtgaatgta tcgggccaaa caagtgcaag tgtcatcctg gttatgctgg  #             450aaaaacctgt aatcaagatc taaatgagtg tggcctgaag ccccggccct  #             500gtaagcacag gtgcatgaac acttacggca gctacaagtg ctactgtctc  #             550aacggatata tgctcatgcc ggatggttcc tgctcaagtg ccctgacctg  #             600ctccatggca aactgtcagt atggctgtga tgttgttaaa ggacaaatac  #             650ggtgccagtg cccatcccct ggcctgcacc tggctcctga tgggaggacc  #             700tgtgtagatg ttgatgaatg tgctacagga agagcctcct gccctagatt  #             750taggcaatgt gtcaacactt ttgggagcta catctgcaag tgtcataaag  #             800gcttcgatct catgtatatt ggaggcaaat atcaatgtca tgacatagac  #             850gaatgctcac ttggtcagta tcagtgcagc agctttgctc gatgttataa  #             900cgtacgtggg tcctacaagt gcaaatgtaa agaaggatac cagggtgatg  #             950gactgacttg tgtgtatatc ccaaaagtta tgattgaacc ttcaggtcca  #            1000attcatgtac caaagggaaa tggtaccatt ttaaagggtg acacaggaaa  #            1050taataattgg attcctgatg ttggaagtac ttggtggcct ccgaagacac  #            1100catatattcc tcctatcatt accaacaggc ctacttctaa gccaacaaca  #            1150agacctacac caaagccaac accaattcct actccaccac caccaccacc  #            1200cctgccaaca gagctcagaa cacctctacc acctacaacc ccagaaaggc  #            1250caaccaccgg actgacaact atagcaccag ctgccagtac acctccagga  #            1300gggattacag ttgacaacag ggtacagaca gaccctcaga aacccagagg  #            1350agatgtgttc agtgttctgg tacacagttg taattttgac catggacttt  #            1400gtggatggat cagggagaaa gacaatgact tgcactggga accaatcagg  #            1450gacccagcag gtggacaata tctgacagtg tcggcagcca aagccccagg  #            1500gggaaaagct gcacgcttgg tgctacctct cggccgcctc atgcattcag  #            1550gggacctgtg cctgtcattc aggcacaagg tgacggggct gcactctggc  #            1600acactccagg tgtttgtgag aaaacacggt gcccacggag cagccctgtg  #            1650gggaagaaat ggtggccatg gctggaggca aacacagatc accttgcgag  #            1700gggctgacat caagagcgaa tcacaaagat gattaaaggg ttggaaaaaa  #            1750agatctatga tggaaaatta aaggaactgg gattattgag cctggagaag  #            1800agaagactga ggggcaaacc attgatggtt ttcaagtata tgaagggttg  #            1850gcacagagag ggtggcgacc agctgttctc catatgcact aagaatagaa  #            1900caagaggaaa ctggcttaga ctagagtata agggagcatt tcttggcagg  #            1950ggccattgtt agaatacttc ataaaaaaag aagtgtgaaa atctcagtat  #            2000ctctctctct ttctaaaaaa ttagataaaa atttgtctat ttaagatggt  #            2050taaagatgtt cttacccaag gaaaagtaac aaattataga atttcccaaa  #            2100agatgttttg atcctactag tagtatgcag tgaaaatctt tagaactaaa  #            2150taatttggac aaggcttaat ttaggcattt ccctcttgac ctcctaatgg  #            2200agagggattg aaaggggaag agcccaccaa atgctgagct cactgaaata  #            2250tctctccctt atggcaatcc tagcagtatt aaagaaaaaa ggaaactatt  #            2300tattccaaat gagagtatga tggacagata ttttagtatc tcagtaatgt  #            2350cctagtgtgg cggtggtttt caatgtttct tcatggtaaa ggtataagcc  #            2400tttcatttgt tcaatggatg atgtttcaga tttttttttt tttaagagat  #            2450ccttcaagga acacagttca gagagatttt catcgggtgc attctctctg  #            2500cttcgtgtgt gacaagttat cttggctgct gagaaagagt gccctgcccc  #            2550acaccggcag acctttcctt cacctcatca gtatgattca gtttctctta  #            2600tcaattggac tctcccaggt tccacagaac agtaatattt tttgaacaat  #            2650aggtacaata gaaggtcttc tgtcatttaa cctggtaaag gcagggctgg  #            2700agggggaaaa taaatcatta agcctttgag taacggcaga atatatggct  #            2750gtagatccat ttttaatggt tcatttcctt tatggtcata taactgcaca  #            2800gctgaagatg aaaggggaaa ataaatgaaa attttacttt tcgatgccaa  #            2850tgatacattg cactaaactg atggaagaag ttatccaaag tactgtataa  #            2900catcttgttt attatttaat gttttctaaa ataaaaaatg ttagtggttt  #            2950tccaaatggc ctaataaaaa caattatttg taaataaaaa cactgttagt  #            3000 aat                   #                  #                   #           3003 <210> SEQ ID NO 315<211> LENGTH: 509 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 315 Met Asp Phe Leu Leu Ala Leu Val Leu Val Se#r Ser Leu Tyr Leu   1               5  #                 10 #                 15 Gln Ala Ala Ala Glu Phe Asp Gly Arg Trp Pr#o Arg Gln Ile Val                  20  #                 25 #                 30 Ser Ser Ile Gly Leu Cys Arg Tyr Gly Gly Ar#g Ile Asp Cys Cys                  35  #                 40 #                 45 Trp Gly Trp Ala Arg Gln Ser Trp Gly Gln Cy#s Gln Pro Val Cys                  50  #                 55 #                 60 Gln Pro Arg Cys Lys His Gly Glu Cys Ile Gl#y Pro Asn Lys Cys                  65  #                 70 #                 75 Lys Cys His Pro Gly Tyr Ala Gly Lys Thr Cy#s Asn Gln Asp Leu                  80  #                 85 #                 90 Asn Glu Cys Gly Leu Lys Pro Arg Pro Cys Ly#s His Arg Cys Met                  95  #                100 #                105 Asn Thr Tyr Gly Ser Tyr Lys Cys Tyr Cys Le#u Asn Gly Tyr Met                 110   #               115  #               120 Leu Met Pro Asp Gly Ser Cys Ser Ser Ala Le#u Thr Cys Ser Met                 125   #               130  #               135 Ala Asn Cys Gln Tyr Gly Cys Asp Val Val Ly#s Gly Gln Ile Arg                 140   #               145  #               150 Cys Gln Cys Pro Ser Pro Gly Leu His Leu Al#a Pro Asp Gly Arg                 155   #               160  #               165 Thr Cys Val Asp Val Asp Glu Cys Ala Thr Gl#y Arg Ala Ser Cys                 170   #               175  #               180 Pro Arg Phe Arg Gln Cys Val Asn Thr Phe Gl#y Ser Tyr Ile Cys                 185   #               190  #               195 Lys Cys His Lys Gly Phe Asp Leu Met Tyr Il#e Gly Gly Lys Tyr                 200   #               205  #               210 Gln Cys His Asp Ile Asp Glu Cys Ser Leu Gl#y Gln Tyr Gln Cys                 215   #               220  #               225 Ser Ser Phe Ala Arg Cys Tyr Asn Val Arg Gl#y Ser Tyr Lys Cys                 230   #               235  #               240 Lys Cys Lys Glu Gly Tyr Gln Gly Asp Gly Le#u Thr Cys Val Tyr                 245   #               250  #               255 Ile Pro Lys Val Met Ile Glu Pro Ser Gly Pr#o Ile His Val Pro                 260   #               265  #               270 Lys Gly Asn Gly Thr Ile Leu Lys Gly Asp Th#r Gly Asn Asn Asn                 275   #               280  #               285 Trp Ile Pro Asp Val Gly Ser Thr Trp Trp Pr#o Pro Lys Thr Pro                 290   #               295  #               300 Tyr Ile Pro Pro Ile Ile Thr Asn Arg Pro Th#r Ser Lys Pro Thr                 305   #               310  #               315 Thr Arg Pro Thr Pro Lys Pro Thr Pro Ile Pr#o Thr Pro Pro Pro                 320   #               325  #               330 Pro Pro Pro Leu Pro Thr Glu Leu Arg Thr Pr#o Leu Pro Pro Thr                 335   #               340  #               345 Thr Pro Glu Arg Pro Thr Thr Gly Leu Thr Th#r Ile Ala Pro Ala                 350   #               355  #               360 Ala Ser Thr Pro Pro Gly Gly Ile Thr Val As#p Asn Arg Val Gln                 365   #               370  #               375 Thr Asp Pro Gln Lys Pro Arg Gly Asp Val Ph#e Ser Val Leu Val                 380   #               385  #               390 His Ser Cys Asn Phe Asp His Gly Leu Cys Gl#y Trp Ile Arg Glu                 395   #               400  #               405 Lys Asp Asn Asp Leu His Trp Glu Pro Ile Ar#g Asp Pro Ala Gly                 410   #               415  #               420 Gly Gln Tyr Leu Thr Val Ser Ala Ala Lys Al#a Pro Gly Gly Lys                 425   #               430  #               435 Ala Ala Arg Leu Val Leu Pro Leu Gly Arg Le#u Met His Ser Gly                 440   #               445  #               450 Asp Leu Cys Leu Ser Phe Arg His Lys Val Th#r Gly Leu His Ser                 455   #               460  #               465 Gly Thr Leu Gln Val Phe Val Arg Lys His Gl#y Ala His Gly Ala                 470   #               475  #               480 Ala Leu Trp Gly Arg Asn Gly Gly His Gly Tr#p Arg Gln Thr Gln                 485   #               490  #               495 Ile Thr Leu Arg Gly Ala Asp Ile Lys Ser Gl#u Ser Gln Arg                 500   #               505<210> SEQ ID NO 316 <211> LENGTH: 24 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 316 gatggttcct gctcaagtgc cctg          #                   #                24 <210> SEQ ID NO 317<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 317 ttgcacttgt aggacccacg tacg          #                   #                24 <210> SEQ ID NO 318<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 318ctgatgggag gacctgtgta gatgttgatg aatgtgctac aggaagagcc  #              50 <210> SEQ ID NO 319 <211> LENGTH: 2110 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 319cttctttgaa aaggattatc acctgatcag gttctctctg catttgcccc  #              50tttagattgt gaaatgtggc tcaaggtctt cacaactttc ctttcctttg  #             100caacaggtgc ttgctcgggg ctgaaggtga cagtgccatc acacactgtc  #             150catggcgtca gaggtcaggc cctctaccta cccgtccact atggcttcca  #             200cactccagca tcagacatcc agatcatatg gctatttgag agaccccaca  #             250caatgcccaa atacttactg ggctctgtga ataagtctgt ggttcctgac  #             300ttggaatacc aacacaagtt caccatgatg ccacccaatg catctctgct  #             350tatcaaccca ctgcagttcc ctgatgaagg caattacatc gtgaaggtca  #             400acattcaggg aaatggaact ctatctgcca gtcagaagat acaagtcacg  #             450gttgatgatc ctgtcacaaa gccagtggtg cagattcatc ctccctctgg  #             500ggctgtggag tatgtgggga acatgaccct gacatgccat gtggaagggg  #             550gcactcggct agcttaccaa tggctaaaaa atgggagacc tgtccacacc  #             600agctccacct actccttttc tccccaaaac aatacccttc atattgctcc  #             650agtaaccaag gaagacattg ggaattacag ctgcctggtg aggaaccctg  #             700tcagtgaaat ggaaagtgat atcattatgc ccatcatata ttatggacct  #             750tatggacttc aagtgaattc tgataaaggg ctaaaagtag gggaagtgtt  #             800tactgttgac cttggagagg ccatcctatt tgattgttct gctgattctc  #             850atccccccaa cacctactcc tggattagga ggactgacaa tactacatat  #             900atcattaagc atgggcctcg cttagaagtt gcatctgaga aagtagccca  #             950gaagacaatg gactatgtgt gctgtgctta caacaacata accggcaggc  #            1000aagatgaaac tcatttcaca gttatcatca cttccgtagg actggagaag  #            1050cttgcacaga aaggaaaatc attgtcacct ttagcaagta taactggaat  #            1100atcactattt ttgattatat ccatgtgtct tctcttccta tggaaaaaat  #            1150atcaacccta caaagttata aaacagaaac tagaaggcag gccagaaaca  #            1200gaatacagga aagctcaaac attttcaggc catgaagatg ctctggatga  #            1250cttcggaata tatgaatttg ttgcttttcc agatgtttct ggtgtttcca  #            1300ggattccaag caggtctgtt ccagcctctg attgtgtatc ggggcaagat  #            1350ttgcacagta cagtgtatga agttattcag cacatccctg cccagcagca  #            1400agaccatcca gagtgaactt tcatgggcta aacagtacat tcgagtgaaa  #            1450ttctgaagaa acattttaag gaaaaacagt ggaaaagtat attaatctgg  #            1500aatcagtgaa gaaaccagga ccaacacctc ttactcatta ttcctttaca  #            1550tgcagaatag aggcatttat gcaaattgaa ctgcaggttt ttcagcatat  #            1600acacaatgtc ttgtgcaaca gaaaaacatg ttggggaaat attcctcagt  #            1650ggagagtcgt tctcatgctg acggggagaa cgaaagtgac aggggtttcc  #            1700tcataagttt tgtatgaaat atctctacaa acctcaatta gttctactct  #            1750acactttcac tatcatcaac actgagacta tcctgtctca cctacaaatg  #            1800tggaaacttt acattgttcg atttttcagc agactttgtt ttattaaatt  #            1850tttattagtg ttaagaatgc taaatttatg tttcaatttt atttccaaat  #            1900ttctatcttg ttatttgtac aacaaagtaa taaggatggt tgtcacaaaa  #            1950acaaaactat gccttctctt ttttttcaat caccagtagt atttttgaga  #            2000agacttgtga acacttaagg aaatgactat taaagtctta tttttatttt  #            2050tttcaaggaa agatggattc aaataaatta ttctgttttt gcttttaaaa  #            2100 aaaaaaaaaa                 #                  #                   #      2110 <210> SEQ ID NO 320 <211> LENGTH: 450<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 320Met Trp Leu Lys Val Phe Thr Thr Phe Leu Se #r Phe Ala Thr Gly  1               5  #                 10  #                 15Ala Cys Ser Gly Leu Lys Val Thr Val Pro Se #r His Thr Val His                 20  #                 25  #                 30Gly Val Arg Gly Gln Ala Leu Tyr Leu Pro Va #l His Tyr Gly Phe                 35  #                 40  #                 45His Thr Pro Ala Ser Asp Ile Gln Ile Ile Tr #p Leu Phe Glu Arg                 50  #                 55  #                 60Pro His Thr Met Pro Lys Tyr Leu Leu Gly Se #r Val Asn Lys Ser                 65  #                 70  #                 75Val Val Pro Asp Leu Glu Tyr Gln His Lys Ph #e Thr Met Met Pro                 80  #                 85  #                 90Pro Asn Ala Ser Leu Leu Ile Asn Pro Leu Gl #n Phe Pro Asp Glu                 95  #                100  #                105Gly Asn Tyr Ile Val Lys Val Asn Ile Gln Gl #y Asn Gly Thr Leu                110   #               115   #               120Ser Ala Ser Gln Lys Ile Gln Val Thr Val As #p Asp Pro Val Thr                125   #               130   #               135Lys Pro Val Val Gln Ile His Pro Pro Ser Gl #y Ala Val Glu Tyr                140   #               145   #               150Val Gly Asn Met Thr Leu Thr Cys His Val Gl #u Gly Gly Thr Arg                155   #               160   #               165Leu Ala Tyr Gln Trp Leu Lys Asn Gly Arg Pr #o Val His Thr Ser                170   #               175   #               180Ser Thr Tyr Ser Phe Ser Pro Gln Asn Asn Th #r Leu His Ile Ala                185   #               190   #               195Pro Val Thr Lys Glu Asp Ile Gly Asn Tyr Se #r Cys Leu Val Arg                200   #               205   #               210Asn Pro Val Ser Glu Met Glu Ser Asp Ile Il #e Met Pro Ile Ile                215   #               220   #               225Tyr Tyr Gly Pro Tyr Gly Leu Gln Val Asn Se #r Asp Lys Gly Leu                230   #               235   #               240Lys Val Gly Glu Val Phe Thr Val Asp Leu Gl #y Glu Ala Ile Leu                245   #               250   #               255Phe Asp Cys Ser Ala Asp Ser His Pro Pro As #n Thr Tyr Ser Trp                260   #               265   #               270Ile Arg Arg Thr Asp Asn Thr Thr Tyr Ile Il #e Lys His Gly Pro                275   #               280   #               285Arg Leu Glu Val Ala Ser Glu Lys Val Ala Gl #n Lys Thr Met Asp                290   #               295   #               300Tyr Val Cys Cys Ala Tyr Asn Asn Ile Thr Gl #y Arg Gln Asp Glu                305   #               310   #               315Thr His Phe Thr Val Ile Ile Thr Ser Val Gl #y Leu Glu Lys Leu                320   #               325   #               330Ala Gln Lys Gly Lys Ser Leu Ser Pro Leu Al #a Ser Ile Thr Gly                335   #               340   #               345Ile Ser Leu Phe Leu Ile Ile Ser Met Cys Le #u Leu Phe Leu Trp                350   #               355   #               360Lys Lys Tyr Gln Pro Tyr Lys Val Ile Lys Gl #n Lys Leu Glu Gly                365   #               370   #               375Arg Pro Glu Thr Glu Tyr Arg Lys Ala Gln Th #r Phe Ser Gly His                380   #               385   #               390Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr Gl #u Phe Val Ala Phe                395   #               400   #               405Pro Asp Val Ser Gly Val Ser Arg Ile Pro Se #r Arg Ser Val Pro                410   #               415   #               420Ala Ser Asp Cys Val Ser Gly Gln Asp Leu Hi #s Ser Thr Val Tyr                425   #               430   #               435Glu Val Ile Gln His Ile Pro Ala Gln Gln Gl #n Asp His Pro Glu                440   #               445   #               450<210> SEQ ID NO 321 <211> LENGTH: 25 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 321 gatcctgtca caaagccagt ggtgc          #                   #               25 <210> SEQ ID NO 322<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 322 cactgacagg gttcctcacc cagg          #                   #               24 <210> SEQ ID NO 323<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 323ctccctctgg gctgtggagt atgtggggaa catgaccctg acatg    #                  #45 <210> SEQ ID NO 324 <211> LENGTH: 2397 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 324gcaagcggcg aaatggcgcc ctccgggagt cttgcagttc ccctggcagt  #              50cctggtgctg ttgctttggg gtgctccctg gacgcacggg cggcggagca  #             100acgttcgcgt catcacggac gagaactgga gagaactgct ggaaggagac  #             150tggatgatag aattttatgc cccgtggtgc cctgcttgtc aaaatcttca  #             200accggaatgg gaaagttttg ctgaatgggg agaagatctt gaggttaata  #             250ttgcgaaagt agatgtcaca gagcagccag gactgagtgg acggtttatc  #             300ataactgctc ttcctactat ttatcattgt aaagatggtg aatttaggcg  #             350ctatcagggt ccaaggacta agaaggactt cataaacttt ataagtgata  #             400aagagtggaa gagtattgag cccgtttcat catggtttgg tccaggttct  #             450gttctgatga gtagtatgtc agcactcttt cagctatcta tgtggatcag  #             500gacgtgccat aactacttta ttgaagacct tggattgcca gtgtggggat  #             550catatactgt ttttgcttta gcaactctgt tttccggact gttattagga  #             600ctctgtatga tatttgtggc agattgcctt tgtccttcaa aaaggcgcag  #             650accacagcca tacccatacc cttcaaaaaa attattatca gaatctgcac  #             700aacctttgaa aaaagtggag gaggaacaag aggcggatga agaagatgtt  #             750tcagaagaag aagctgaaag taaagaagga acaaacaaag actttccaca  #             800gaatgccata agacaacgct ctctgggtcc atcattggcc acagataaat  #             850cctagttaaa ttttatagtt atcttaatat tatgattttg ataaaaacag  #             900aagattgatc attttgtttg gtttgaagtg aactgtgact tttttgaata  #             950ttgcagggtt cagtctagat tgtcattaaa ttgaagagtc tacattcaga  #            1000acataaaagc actaggtata caagtttgaa atatgattta agcacagtat  #            1050gatggtttaa atagttctct aatttttgaa aaatcgtgcc aagcaataag  #            1100atttatgtat atttgtttaa taataaccta tttcaagtct gagttttgaa  #            1150aatttacatt tcccaagtat tgcattattg aggtatttaa gaagattatt  #            1200ttagagaaaa atatttctca tttgatataa tttttctctg tttcactgtg  #            1250tgaaaaaaag aagatatttc ccataaatgg gaagtttgcc cattgtctca  #            1300agaaatgtgt atttcagtga caatttcgtg gtctttttag aggtatattc  #            1350caaaatttcc ttgtattttt aggttatgca actaataaaa actaccttac  #            1400attaattaat tacagttttc tacacatggt aatacaggat atgctactga  #            1450tttaggaagt ttttaagttc atggtattct cttgattcca acaaagtttg  #            1500attttctctt gtatttttct tacttactat gggttacatt ttttattttt  #            1550caaattggat gataatttct tggaaacatt ttttatgttt tagtaaacag  #            1600tatttttttg ttgtttcaaa ctgaagttta ctgagagatc catcaaattg  #            1650aacaatctgt tgtaatttaa aattttggcc acttttttca gattttacat  #            1700cattcttgct gaacttcaac ttgaaattgt tttttttttc tttttggatg  #            1750tgaaggtgaa cattcctgat ttttgtctga tgtgaaaaag ccttggtatt  #            1800ttacattttg aaaattcaaa gaagcttaat ataaaagttt gcattctact  #            1850caggaaaaag catcttcttg tatatgtctt aaatgtattt ttgtcctcat  #            1900atacagaaag ttcttaattg attttacagt ctgtaatgct tgatgtttta  #            1950aaataataac atttttatat tttttaaaag acaaacttca tattatcctg  #            2000tgttctttcc tgactggtaa tattgtgtgg gatttcacag gtaaaagtca  #            2050gtaggatgga acattttagt gtatttttac tccttaaaga gctagaatac  #            2100atagttttca ccttaaaaga agggggaaaa tcataaatac aatgaatcaa  #            2150ctgaccatta cgtagtagac aatttctgta atgtcccctt ctttctaggc  #            2200tctgttgctg tgtgaatcca ttagatttac agtatcgtaa tatacaagtt  #            2250ttctttaaag ccctctcctt tagaatttaa aatattgtac cattaaagag  #            2300tttggatgtg taacttgtga tgccttagaa aaatatccta agcacaaaat  #            2350 aaacctttct aaccacttca ttaaagctga aaaaaaaaaa aaaaaaa   #              2397 <210> SEQ ID NO 325 <211> LENGTH: 280<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 325Met Ala Pro Ser Gly Ser Leu Ala Val Pro Le #u Ala Val Leu Val  1               5  #                 10  #                 15Leu Leu Leu Trp Gly Ala Pro Trp Thr His Gl #y Arg Arg Ser Asn                 20  #                 25  #                 30Val Arg Val Ile Thr Asp Glu Asn Trp Arg Gl #u Leu Leu Glu Gly                 35  #                 40  #                 45Asp Trp Met Ile Glu Phe Tyr Ala Pro Trp Cy #s Pro Ala Cys Gln                 50  #                 55  #                 60Asn Leu Gln Pro Glu Trp Glu Ser Phe Ala Gl #u Trp Gly Glu Asp                 65  #                 70  #                 75Leu Glu Val Asn Ile Ala Lys Val Asp Val Th #r Glu Gln Pro Gly                 80  #                 85  #                 90Leu Ser Gly Arg Phe Ile Ile Thr Ala Leu Pr #o Thr Ile Tyr His                 95  #                100  #                105Cys Lys Asp Gly Glu Phe Arg Arg Tyr Gln Gl #y Pro Arg Thr Lys                110   #               115   #               120Lys Asp Phe Ile Asn Phe Ile Ser Asp Lys Gl #u Trp Lys Ser Ile                125   #               130   #               135Glu Pro Val Ser Ser Trp Phe Gly Pro Gly Se #r Val Leu Met Ser                140   #               145   #               150Ser Met Ser Ala Leu Phe Gln Leu Ser Met Tr #p Ile Arg Thr Cys                155   #               160   #               165His Asn Tyr Phe Ile Glu Asp Leu Gly Leu Pr #o Val Trp Gly Ser                170   #               175   #               180Tyr Thr Val Phe Ala Leu Ala Thr Leu Phe Se #r Gly Leu Leu Leu                185   #               190   #               195Gly Leu Cys Met Ile Phe Val Ala Asp Cys Le #u Cys Pro Ser Lys                200   #               205   #               210Arg Arg Arg Pro Gln Pro Tyr Pro Tyr Pro Se #r Lys Lys Leu Leu                215   #               220   #               225Ser Glu Ser Ala Gln Pro Leu Lys Lys Val Gl #u Glu Glu Gln Glu                230   #               235   #               240Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Al #a Glu Ser Lys Glu                245   #               250   #               255Gly Thr Asn Lys Asp Phe Pro Gln Asn Ala Il #e Arg Gln Arg Ser                260   #               265   #               270Leu Gly Pro Ser Leu Ala Thr Asp Lys Ser                 275  #               280 <210> SEQ ID NO 326 <211> LENGTH: 23 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 326 tgaggtgggc aagcggcgaa atg           #                   #                23 <210> SEQ ID NO 327<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 327 tatgtggatc aggacgtgcc            #                   #                   # 20 <210> SEQ ID NO 328<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 328 tgcagggttc agtctagatt g           #                   #                   #21 <210> SEQ ID NO 329<211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 329 ttgaaggaca aaggcaatct gccac          #                   #               25 <210> SEQ ID NO 330<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 330ggagtcttgc agttcccctg gcagtcctgg tgctgttgct ttggg    #                  #45 <210> SEQ ID NO 331 <211> LENGTH: 2168 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 331gcgagtgtcc agctgcggag acccgtgata attcgttaac taattcaaca  #              50aacgggaccc ttctgtgtgc cagaaaccgc aagcagttgc taacccagtg  #             100ggacaggcgg attggaagag cgggaaggtc ctggcccaga gcagtgtgac  #             150acttccctct gtgaccatga aactctgggt gtctgcattg ctgatggcct  #             200ggtttggtgt cctgagctgt gtgcaggccg aattcttcac ctctattggg  #             250cacatgactg acctgattta tgcagagaaa gagctggtgc agtctctgaa  #             300agagtacatc cttgtggagg aagccaagct ttccaagatt aagagctggg  #             350ccaacaaaat ggaagccttg actagcaagt cagctgctga tgctgagggc  #             400tacctggctc accctgtgaa tgcctacaaa ctggtgaagc ggctaaacac  #             450agactggcct gcgctggagg accttgtcct gcaggactca gctgcaggtt  #             500ttatcgccaa cctctctgtg cagcggcagt tcttccccac tgatgaggac  #             550gagataggag ctgccaaagc cctgatgaga cttcaggaca catacaggct  #             600ggacccaggc acaatttcca gaggggaact tccaggaacc aagtaccagg  #             650caatgctgag tgtggatgac tgctttggga tgggccgctc ggcctacaat  #             700gaaggggact attatcatac ggtgttgtgg atggagcagg tgctaaagca  #             750gcttgatgcc ggggaggagg ccaccacaac caagtcacag gtgctggact  #             800acctcagcta tgctgtcttc cagttgggtg atctgcaccg tgccctggag  #             850ctcacccgcc gcctgctctc ccttgaccca agccacgaac gagctggagg  #             900gaatctgcgg tactttgagc agttattgga ggaagagaga gaaaaaacgt  #             950taacaaatca gacagaagct gagctagcaa ccccagaagg catctatgag  #            1000aggcctgtgg actacctgcc tgagagggat gtttacgaga gcctctgtcg  #            1050tggggagggt gtcaaactga caccccgtag acagaagagg cttttctgta  #            1100ggtaccacca tggcaacagg gccccacagc tgctcattgc ccccttcaaa  #            1150gaggaggacg agtgggacag cccgcacatc gtcaggtact acgatgtcat  #            1200gtctgatgag gaaatcgaga ggatcaagga gatcgcaaaa cctaaacttg  #            1250cacgagccac cgttcgtgat cccaagacag gagtcctcac tgtcgccagc  #            1300taccgggttt ccaaaagctc ctggctagag gaagatgatg accctgttgt  #            1350ggcccgagta aatcgtcgga tgcagcatat cacagggtta acagtaaaga  #            1400ctgcagaatt gttacaggtt gcaaattatg gagtgggagg acagtatgaa  #            1450ccgcacttcg acttctctag gcgacctttt gacagcggcc tcaaaacaga  #            1500ggggaatagg ttagcgacgt ttcttaacta catgagtgat gtagaagctg  #            1550gtggtgccac cgtcttccct gatctggggg ctgcaatttg gcctaagaag  #            1600ggtacagctg tgttctggta caacctcttg cggagcgggg aaggtgacta  #            1650ccgaacaaga catgctgcct gccctgtgct tgtgggctgc aagtgggtct  #            1700ccaataagtg gttccatgaa cgaggacagg agttcttgag accttgtgga  #            1750tcaacagaag ttgactgaca tccttttctg tccttcccct tcctggtcct  #            1800tcagcccatg tcaacgtgac agacaccttt gtatgttcct ttgtatgttc  #            1850ctatcaggct gatttttgga gaaatgaatg tttgtctgga gcagagggag  #            1900accatactag ggcgactcct gtgtgactga agtcccagcc cttccattca  #            1950gcctgtgcca tccctggccc caaggctagg atcaaagtgg ctgcagcaga  #            2000gttagctgtc tagcgcctag caaggtgcct ttgtacctca ggtgttttag  #            2050gtgtgagatg tttcagtgaa ccaaagttct gataccttgt ttacatgttt  #            2100gtttttatgg catttctatc tattgtggct ttaccaaaaa ataaaatgtc  #            2150 cctaccagaa aaaaaaaa              #                  #                   #2168 <210> SEQ ID NO 332 <211> LENGTH: 533<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 332Met Lys Leu Trp Val Ser Ala Leu Leu Met Al #a Trp Phe Gly Val  1               5  #                 10  #                 15Leu Ser Cys Val Gln Ala Glu Phe Phe Thr Se #r Ile Gly His Met                 20  #                 25  #                 30Thr Asp Leu Ile Tyr Ala Glu Lys Glu Leu Va #l Gln Ser Leu Lys                 35  #                 40  #                 45Glu Tyr Ile Leu Val Glu Glu Ala Lys Leu Se #r Lys Ile Lys Ser                 50  #                 55  #                 60Trp Ala Asn Lys Met Glu Ala Leu Thr Ser Ly #s Ser Ala Ala Asp                 65  #                 70  #                 75Ala Glu Gly Tyr Leu Ala His Pro Val Asn Al #a Tyr Lys Leu Val                 80  #                 85  #                 90Lys Arg Leu Asn Thr Asp Trp Pro Ala Leu Gl #u Asp Leu Val Leu                 95  #                100  #                105Gln Asp Ser Ala Ala Gly Phe Ile Ala Asn Le #u Ser Val Gln Arg                110   #               115   #               120Gln Phe Phe Pro Thr Asp Glu Asp Glu Ile Gl #y Ala Ala Lys Ala                125   #               130   #               135Leu Met Arg Leu Gln Asp Thr Tyr Arg Leu As #p Pro Gly Thr Ile                140   #               145   #               150Ser Arg Gly Glu Leu Pro Gly Thr Lys Tyr Gl #n Ala Met Leu Ser                155   #               160   #               165Val Asp Asp Cys Phe Gly Met Gly Arg Ser Al #a Tyr Asn Glu Gly                170   #               175   #               180Asp Tyr Tyr His Thr Val Leu Trp Met Glu Gl #n Val Leu Lys Gln                185   #               190   #               195Leu Asp Ala Gly Glu Glu Ala Thr Thr Thr Ly #s Ser Gln Val Leu                200   #               205   #               210Asp Tyr Leu Ser Tyr Ala Val Phe Gln Leu Gl #y Asp Leu His Arg                215   #               220   #               225Ala Leu Glu Leu Thr Arg Arg Leu Leu Ser Le #u Asp Pro Ser His                230   #               235   #               240Glu Arg Ala Gly Gly Asn Leu Arg Tyr Phe Gl #u Gln Leu Leu Glu                245   #               250   #               255Glu Glu Arg Glu Lys Thr Leu Thr Asn Gln Th #r Glu Ala Glu Leu                260   #               265   #               270Ala Thr Pro Glu Gly Ile Tyr Glu Arg Pro Va #l Asp Tyr Leu Pro                275   #               280   #               285Glu Arg Asp Val Tyr Glu Ser Leu Cys Arg Gl #y Glu Gly Val Lys                290   #               295   #               300Leu Thr Pro Arg Arg Gln Lys Arg Leu Phe Cy #s Arg Tyr His His                305   #               310   #               315Gly Asn Arg Ala Pro Gln Leu Leu Ile Ala Pr #o Phe Lys Glu Glu                320   #               325   #               330Asp Glu Trp Asp Ser Pro His Ile Val Arg Ty #r Tyr Asp Val Met                335   #               340   #               345Ser Asp Glu Glu Ile Glu Arg Ile Lys Glu Il #e Ala Lys Pro Lys                350   #               355   #               360Leu Ala Arg Ala Thr Val Arg Asp Pro Lys Th #r Gly Val Leu Thr                365   #               370   #               375Val Ala Ser Tyr Arg Val Ser Lys Ser Ser Tr #p Leu Glu Glu Asp                380   #               385   #               390Asp Asp Pro Val Val Ala Arg Val Asn Arg Ar #g Met Gln His Ile                395   #               400   #               405Thr Gly Leu Thr Val Lys Thr Ala Glu Leu Le #u Gln Val Ala Asn                410   #               415   #               420Tyr Gly Val Gly Gly Gln Tyr Glu Pro His Ph #e Asp Phe Ser Arg                425   #               430   #               435Arg Pro Phe Asp Ser Gly Leu Lys Thr Glu Gl #y Asn Arg Leu Ala                440   #               445   #               450Thr Phe Leu Asn Tyr Met Ser Asp Val Glu Al #a Gly Gly Ala Thr                455   #               460   #               465Val Phe Pro Asp Leu Gly Ala Ala Ile Trp Pr #o Lys Lys Gly Thr                470   #               475   #               480Ala Val Phe Trp Tyr Asn Leu Leu Arg Ser Gl #y Glu Gly Asp Tyr                485   #               490   #               495Arg Thr Arg His Ala Ala Cys Pro Val Leu Va #l Gly Cys Lys Trp                500   #               505   #               510Val Ser Asn Lys Trp Phe His Glu Arg Gly Gl #n Glu Phe Leu Arg                515   #               520   #               525Pro Cys Gly Ser Thr Glu Val Asp                 530 <210> SEQ ID NO 333<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 333 ccaggcacaa tttccaga             #                   #                   #  18 <210> SEQ ID NO 334<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 334 ggacccttct gtgtgccag             #                   #                   # 19 <210> SEQ ID NO 335<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 335 ggtctcaaga actcctgtc             #                   #                   # 19 <210> SEQ ID NO 336<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 336 acactcagca ttgcctggta cttg          #                   #                24 <210> SEQ ID NO 337<211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 337gggcacatga ctgacctgat ttatgcagag aaagagctgg tgcag    #                  #45 <210> SEQ ID NO 338 <211> LENGTH: 2789 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <400> SEQUENCE: 338gcagtattga gttttacttc ctcctctttt tagtggaaga cagaccataa  #              50tcccagtgtg agtgaaattg attgtttcat ttattaccgt tttggctggg  #             100ggttagttcc gacaccttca cagttgaaga gcaggcagaa ggagttgtga  #             150agacaggaca atcttcttgg ggatgctggt cctggaagcc agcgggcctt  #             200gctctgtctt tggcctcatt gaccccaggt tctctggtta aaactgaaag  #             250cctactactg gcctggtgcc catcaatcca ttgatccttg aggctgtgcc  #             300cctggggcac ccacctggca gggcctacca ccatgcgact gagctccctg  #             350ttggctctgc tgcggccagc gcttcccctc atcttagggc tgtctctggg  #             400gtgcagcctg agcctcctgc gggtttcctg gatccagggg gagggagaag  #             450atccctgtgt cgaggctgta ggggagcgag gagggccaca gaatccagat  #             500tcgagagctc ggctagacca aagtgatgaa gacttcaaac cccggattgt  #             550cccctactac agggacccca acaagcccta caagaaggtg ctcaggactc  #             600ggtacatcca gacagagctg ggctcccgtg agcggttgct ggtggctgtc  #             650ctgacctccc gagctacact gtccactttg gccgtggctg tgaaccgtac  #             700ggtggcccat cacttccctc ggttactcta cttcactggg cagcgggggg  #             750cccgggctcc agcagggatg caggtggtgt ctcatgggga tgagcggccc  #             800gcctggctca tgtcagagac cctgcgccac cttcacacac actttggggc  #             850cgactacgac tggttcttca tcatgcagga tgacacatat gtgcaggccc  #             900cccgcctggc agcccttgct ggccacctca gcatcaacca agacctgtac  #             950ttaggccggg cagaggagtt cattggcgca ggcgagcagg cccggtactg  #            1000tcatgggggc tttggctacc tgttgtcacg gagtctcctg cttcgtctgc  #            1050ggccacatct ggatggctgc cgaggagaca ttctcagtgc ccgtcctgac  #            1100gagtggcttg gacgctgcct cattgactct ctgggcgtcg gctgtgtctc  #            1150acagcaccag gggcagcagt atcgctcatt tgaactggcc aaaaataggg  #            1200accctgagaa ggaagggagc tcggctttcc tgagtgcctt cgccgtgcac  #            1250cctgtctccg aaggtaccct catgtaccgg ctccacaaac gcttcagcgc  #            1300tctggagttg gagcgggctt acagtgaaat agaacaactg caggctcaga  #            1350tccggaacct gaccgtgctg acccccgaag gggaggcagg gctgagctgg  #            1400cccgttgggc tccctgctcc tttcacacca cactctcgct ttgaggtgct  #            1450gggctgggac tacttcacag agcagcacac cttctcctgt gcagatgggg  #            1500ctcccaagtg cccactacag ggggctagca gggcggacgt gggtgatgcg  #            1550ttggagactg ccctggagca gctcaatcgg cgctatcagc cccgcctgcg  #            1600cttccagaag cagcgactgc tcaacggcta tcggcgcttc gacccagcac  #            1650ggggcatgga gtacaccctg gacctgctgt tggaatgtgt gacacagcgt  #            1700gggcaccggc gggccctggc tcgcagggtc agcctgctgc ggccactgag  #            1750ccgggtggaa atcctaccta tgccctatgt cactgaggcc acccgagtgc  #            1800agctggtgct gccactcctg gtggctgaag ctgctgcagc cccggctttc  #            1850ctcgaggcgt ttgcagccaa tgtcctggag ccacgagaac atgcattgct  #            1900caccctgttg ctggtctacg ggccacgaga aggtggccgt ggagctccag  #            1950acccatttct tggggtgaag gctgcagcag cggagttaga gcgacggtac  #            2000cctgggacga ggctggcctg gctcgctgtg cgagcagagg ccccttccca  #            2050ggtgcgactc atggacgtgg tctcgaagaa gcaccctgtg gacactctct  #            2100tcttccttac caccgtgtgg acaaggcctg ggcccgaagt cctcaaccgc  #            2150tgtcgcatga atgccatctc tggctggcag gccttctttc cagtccattt  #            2200ccaggagttc aatcctgccc tgtcaccaca gagatcaccc ccagggcccc  #            2250cgggggctgg ccctgacccc ccctcccctc ctggtgctga cccctcccgg  #            2300ggggctccta taggggggag atttgaccgg caggcttctg cggagggctg  #            2350cttctacaac gctgactacc tggcggcccg agcccggctg gcaggtgaac  #            2400tggcaggcca ggaagaggag gaagccctgg aggggctgga ggtgatggat  #            2450gttttcctcc ggttctcagg gctccacctc tttcgggccg tagagccagg  #            2500gctggtgcag aagttctccc tgcgagactg cagcccacgg ctcagtgaag  #            2550aactctacca ccgctgccgc ctcagcaacc tggaggggct agggggccgt  #            2600gcccagctgg ctatggctct ctttgagcag gagcaggcca atagcactta  #            2650gcccgcctgg gggccctaac ctcattacct ttcctttgtc tgcctcagcc  #            2700ccaggaaggg caaggcaaga tggtggacag atagagaatt gttgctgtat  #            2750 tttttaaata tgaaaatgtt attaaacatg tcttctgcc      #                   #  2789 <210> SEQ ID NO 339 <211> LENGTH: 772<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 339Met Arg Leu Ser Ser Leu Leu Ala Leu Leu Ar #g Pro Ala Leu Pro  1               5  #                 10  #                 15Leu Ile Leu Gly Leu Ser Leu Gly Cys Ser Le #u Ser Leu Leu Arg                 20  #                 25  #                 30Val Ser Trp Ile Gln Gly Glu Gly Glu Asp Pr #o Cys Val Glu Ala                 35  #                 40  #                 45Val Gly Glu Arg Gly Gly Pro Gln Asn Pro As #p Ser Arg Ala Arg                 50  #                 55  #                 60Leu Asp Gln Ser Asp Glu Asp Phe Lys Pro Ar #g Ile Val Pro Tyr                 65  #                 70  #                 75Tyr Arg Asp Pro Asn Lys Pro Tyr Lys Lys Va #l Leu Arg Thr Arg                 80  #                 85  #                 90Tyr Ile Gln Thr Glu Leu Gly Ser Arg Glu Ar #g Leu Leu Val Ala                 95  #                100  #                105Val Leu Thr Ser Arg Ala Thr Leu Ser Thr Le #u Ala Val Ala Val                110   #               115   #               120Asn Arg Thr Val Ala His His Phe Pro Arg Le #u Leu Tyr Phe Thr                125   #               130   #               135Gly Gln Arg Gly Ala Arg Ala Pro Ala Gly Me #t Gln Val Val Ser                140   #               145   #               150His Gly Asp Glu Arg Pro Ala Trp Leu Met Se #r Glu Thr Leu Arg                155   #               160   #               165His Leu His Thr His Phe Gly Ala Asp Tyr As #p Trp Phe Phe Ile                170   #               175   #               180Met Gln Asp Asp Thr Tyr Val Gln Ala Pro Ar #g Leu Ala Ala Leu                185   #               190   #               195Ala Gly His Leu Ser Ile Asn Gln Asp Leu Ty #r Leu Gly Arg Ala                200   #               205   #               210Glu Glu Phe Ile Gly Ala Gly Glu Gln Ala Ar #g Tyr Cys His Gly                215   #               220   #               225Gly Phe Gly Tyr Leu Leu Ser Arg Ser Leu Le #u Leu Arg Leu Arg                230   #               235   #               240Pro His Leu Asp Gly Cys Arg Gly Asp Ile Le #u Ser Ala Arg Pro                245   #               250   #               255Asp Glu Trp Leu Gly Arg Cys Leu Ile Asp Se #r Leu Gly Val Gly                260   #               265   #               270Cys Val Ser Gln His Gln Gly Gln Gln Tyr Ar #g Ser Phe Glu Leu                275   #               280   #               285Ala Lys Asn Arg Asp Pro Glu Lys Glu Gly Se #r Ser Ala Phe Leu                290   #               295   #               300Ser Ala Phe Ala Val His Pro Val Ser Glu Gl #y Thr Leu Met Tyr                305   #               310   #               315Arg Leu His Lys Arg Phe Ser Ala Leu Glu Le #u Glu Arg Ala Tyr                320   #               325   #               330Ser Glu Ile Glu Gln Leu Gln Ala Gln Ile Ar #g Asn Leu Thr Val                335   #               340   #               345Leu Thr Pro Glu Gly Glu Ala Gly Leu Ser Tr #p Pro Val Gly Leu                350   #               355   #               360Pro Ala Pro Phe Thr Pro His Ser Arg Phe Gl #u Val Leu Gly Trp                365   #               370   #               375Asp Tyr Phe Thr Glu Gln His Thr Phe Ser Cy #s Ala Asp Gly Ala                380   #               385   #               390Pro Lys Cys Pro Leu Gln Gly Ala Ser Arg Al #a Asp Val Gly Asp                395   #               400   #               405Ala Leu Glu Thr Ala Leu Glu Gln Leu Asn Ar #g Arg Tyr Gln Pro                410   #               415   #               420Arg Leu Arg Phe Gln Lys Gln Arg Leu Leu As #n Gly Tyr Arg Arg                425   #               430   #               435Phe Asp Pro Ala Arg Gly Met Glu Tyr Thr Le #u Asp Leu Leu Leu                440   #               445   #               450Glu Cys Val Thr Gln Arg Gly His Arg Arg Al #a Leu Ala Arg Arg                455   #               460   #               465Val Ser Leu Leu Arg Pro Leu Ser Arg Val Gl #u Ile Leu Pro Met                470   #               475   #               480Pro Tyr Val Thr Glu Ala Thr Arg Val Gln Le #u Val Leu Pro Leu                485   #               490   #               495Leu Val Ala Glu Ala Ala Ala Ala Pro Ala Ph #e Leu Glu Ala Phe                500   #               505   #               510Ala Ala Asn Val Leu Glu Pro Arg Glu His Al #a Leu Leu Thr Leu                515   #               520   #               525Leu Leu Val Tyr Gly Pro Arg Glu Gly Gly Ar #g Gly Ala Pro Asp                530   #               535   #               540Pro Phe Leu Gly Val Lys Ala Ala Ala Ala Gl #u Leu Glu Arg Arg                545   #               550   #               555Tyr Pro Gly Thr Arg Leu Ala Trp Leu Ala Va #l Arg Ala Glu Ala                560   #               565   #               570Pro Ser Gln Val Arg Leu Met Asp Val Val Se #r Lys Lys His Pro                575   #               580   #               585Val Asp Thr Leu Phe Phe Leu Thr Thr Val Tr #p Thr Arg Pro Gly                590   #               595   #               600Pro Glu Val Leu Asn Arg Cys Arg Met Asn Al #a Ile Ser Gly Trp                605   #               610   #               615Gln Ala Phe Phe Pro Val His Phe Gln Glu Ph #e Asn Pro Ala Leu                620   #               625   #               630Ser Pro Gln Arg Ser Pro Pro Gly Pro Pro Gl #y Ala Gly Pro Asp                635   #               640   #               645Pro Pro Ser Pro Pro Gly Ala Asp Pro Ser Ar #g Gly Ala Pro Ile                650   #               655   #               660Gly Gly Arg Phe Asp Arg Gln Ala Ser Ala Gl #u Gly Cys Phe Tyr                665   #               670   #               675Asn Ala Asp Tyr Leu Ala Ala Arg Ala Arg Le #u Ala Gly Glu Leu                680   #               685   #               690Ala Gly Gln Glu Glu Glu Glu Ala Leu Glu Gl #y Leu Glu Val Met                695   #               700   #               705Asp Val Phe Leu Arg Phe Ser Gly Leu His Le #u Phe Arg Ala Val                710   #               715   #               720Glu Pro Gly Leu Val Gln Lys Phe Ser Leu Ar #g Asp Cys Ser Pro                725   #               730   #               735Arg Leu Ser Glu Glu Leu Tyr His Arg Cys Ar #g Leu Ser Asn Leu                740   #               745   #               750Glu Gly Leu Gly Gly Arg Ala Gln Leu Ala Me #t Ala Leu Phe Glu                755   #               760   #               765Gln Glu Gln Ala Asn Ser Thr                 770 <210> SEQ ID NO 340<211> LENGTH: 1572 <212> TYPE: DNA <213> ORGANISM: Homo Sapien<400> SEQUENCE: 340cggagtggtg cgccaacgtg agaggaaacc cgtgcgcggc tgcgctttcc  #              50tgtccccaag ccgttctaga cgcgggaaaa atgctttctg aaagcagctc  #             100ctttttgaag ggtgtgatgc ttggaagcat tttctgtgct ttgatcacta  #             150tgctaggaca cattaggatt ggtcatggaa atagaatgca ccaccatgag  #             200catcatcacc tacaagctcc taacaaagaa gatatcttga aaatttcaga  #             250ggatgagcgc atggagctca gtaagagctt tcgagtatac tgtattatcc  #             300ttgtaaaacc caaagatgtg agtctttggg ctgcagtaaa ggagacttgg  #             350accaaacact gtgacaaagc agagttcttc agttctgaaa atgttaaagt  #             400gtttgagtca attaatatgg acacaaatga catgtggtta atgatgagaa  #             450aagcttacaa atacgccttt gataagtata gagaccaata caactggttc  #             500ttccttgcac gccccactac gtttgctatc attgaaaacc taaagtattt  #             550tttgttaaaa aaggatccat cacagccttt ctatctaggc cacactataa  #             600aatctggaga ccttgaatat gtgggtatgg aaggaggaat tgtcttaagt  #             650gtagaatcaa tgaaaagact taacagcctt ctcaatatcc cagaaaagtg  #             700tcctgaacag ggagggatga tttggaagat atctgaagat aaacagctag  #             750cagtttgcct gaaatatgct ggagtatttg cagaaaatgc agaagatgct  #             800gatggaaaag atgtatttaa taccaaatct gttgggcttt ctattaaaga  #             850ggcaatgact tatcacccca accaggtagt agaaggctgt tgttcagata  #             900tggctgttac ttttaatgga ctgactccaa atcagatgca tgtgatgatg  #             950tatggggtat accgccttag ggcatttggg catattttca atgatgcatt  #            1000ggttttctta cctccaaatg gttctgacaa tgactgagaa gtggtagaaa  #            1050agcgtgaata tgatctttgt ataggacgtg tgttgtcatt atttgtagta  #            1100gtaactacat atccaataca gctgtatgtt tctttttctt ttctaatttg  #            1150gtggcactgg tataaccaca cattaaagtc agtagtacat ttttaaatga  #            1200gggtggtttt tttctttaaa acacatgaac attgtaaatg tgttggaaag  #            1250aagtgtttta agaataataa ttttgcaaat aaactattaa taaatattat  #            1300atgtgataaa ttctaaatta tgaacattag aaatctgtgg ggcacatatt  #            1350tttgctgatt ggttaaaaaa ttttaacagg tctttagcgt tctaagatat  #            1400gcaaatgata tctctagttg tgaatttgtg attaaagtaa aacttttagc  #            1450tgtgtgttcc ctttacttct aatactgatt tatgttctaa gcctccccaa  #            1500gttccaatgg atttgccttc tcaaaatgta caactaagca actaaagaaa  #            1550 attaaagtga aagttgaaaa at           #                   #               1572 <210> SEQ ID NO 341<211> LENGTH: 318 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 341 Met Leu Ser Glu Ser Ser Ser Phe Leu Lys Gl#y Val Met Leu Gly   1               5  #                 10 #                 15 Ser Ile Phe Cys Ala Leu Ile Thr Met Leu Gl#y His Ile Arg Ile                  20  #                 25 #                 30 Gly His Gly Asn Arg Met His His His Glu Hi#s His His Leu Gln                  35  #                 40 #                 45 Ala Pro Asn Lys Glu Asp Ile Leu Lys Ile Se#r Glu Asp Glu Arg                  50  #                 55 #                 60 Met Glu Leu Ser Lys Ser Phe Arg Val Tyr Cy#s Ile Ile Leu Val                  65  #                 70 #                 75 Lys Pro Lys Asp Val Ser Leu Trp Ala Ala Va#l Lys Glu Thr Trp                  80  #                 85 #                 90 Thr Lys His Cys Asp Lys Ala Glu Phe Phe Se#r Ser Glu Asn Val                  95  #                100 #                105 Lys Val Phe Glu Ser Ile Asn Met Asp Thr As#n Asp Met Trp Leu                 110   #               115  #               120 Met Met Arg Lys Ala Tyr Lys Tyr Ala Phe As#p Lys Tyr Arg Asp                 125   #               130  #               135 Gln Tyr Asn Trp Phe Phe Leu Ala Arg Pro Th#r Thr Phe Ala Ile                 140   #               145  #               150 Ile Glu Asn Leu Lys Tyr Phe Leu Leu Lys Ly#s Asp Pro Ser Gln                 155   #               160  #               165 Pro Phe Tyr Leu Gly His Thr Ile Lys Ser Gl#y Asp Leu Glu Tyr                 170   #               175  #               180 Val Gly Met Glu Gly Gly Ile Val Leu Ser Va#l Glu Ser Met Lys                 185   #               190  #               195 Arg Leu Asn Ser Leu Leu Asn Ile Pro Glu Ly#s Cys Pro Glu Gln                 200   #               205  #               210 Gly Gly Met Ile Trp Lys Ile Ser Glu Asp Ly#s Gln Leu Ala Val                 215   #               220  #               225 Cys Leu Lys Tyr Ala Gly Val Phe Ala Glu As#n Ala Glu Asp Ala                 230   #               235  #               240 Asp Gly Lys Asp Val Phe Asn Thr Lys Ser Va#l Gly Leu Ser Ile                 245   #               250  #               255 Lys Glu Ala Met Thr Tyr His Pro Asn Gln Va#l Val Glu Gly Cys                 260   #               265  #               270 Cys Ser Asp Met Ala Val Thr Phe Asn Gly Le#u Thr Pro Asn Gln                 275   #               280  #               285 Met His Val Met Met Tyr Gly Val Tyr Arg Le#u Arg Ala Phe Gly                 290   #               295  #               300 His Ile Phe Asn Asp Ala Leu Val Phe Leu Pr#o Pro Asn Gly Ser                 305   #               310  #               315 Asp Asn Asp <210> SEQ ID NO 342 <211> LENGTH: 23<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 342 tccccaagcc gttctagacg cgg           #                   #                23 <210> SEQ ID NO 343<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 343 ctggttcttc cttgcacg             #                   #                   #  18 <210> SEQ ID NO 344<211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 344 gcccaaatgc cctaaggcgg tatacccc         #                   #             28 <210> SEQ ID NO 345<211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 345gggtgtgatg cttggaagca ttttctgtgc tttgatcact atgctaggac  #              50 <210> SEQ ID NO 346 <211> LENGTH: 25 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 346 gggatgcagg tggtgtctca tgggg          #                   #               25 <210> SEQ ID NO 347<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 347 ccctcatgta ccggctcc             #                   #                   #  18 <210> SEQ ID NO 348<211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 348ggattctaat acgactcact atagggctca gaaaagcgca acagagaa  #                48 <210> SEQ ID NO 349 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 349ctatgaaatt aaccctcact aaagggatgt cttccatgcc aaccttc   #                47 <210> SEQ ID NO 350 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 350ggattctaat acgactcact atagggcggc gatgtccact ggggctac  #                48 <210> SEQ ID NO 351 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 351ctatgaaatt aaccctcact aaagggacga ggaagatggg cggatggt  #                48 <210> SEQ ID NO 352 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 352ggattctaat acgactcact atagggcacc cacgcgtccg gctgctt   #                47 <210> SEQ ID NO 353 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 353ctatgaaatt aaccctcact aaagggacgg gggacaccac ggaccaga  #                48 <210> SEQ ID NO 354 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 354ggattctaat acgactcact atagggcttg ctgcggtttt tgttcctg  #                48 <210> SEQ ID NO 355 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 355ctatgaaatt aaccctcact aaagggagct gccgatccca ctggtatt  #                48 <210> SEQ ID NO 356 <211> LENGTH: 46 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 356ggattctaat acgactcact atagggcgga tcctggccgg cctctg   #                 46 <210> SEQ ID NO 357 <211> LENGTH: 48<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 357ctatgaaatt aaccctcact aaagggagcc cgggcatggt ctcagtta  #                48 <210> SEQ ID NO 358 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 358ggattctaat acgactcact atagggcggg aagatggcga ggaggag   #                47 <210> SEQ ID NO 359 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 359ctatgaaatt aaccctcact aaagggacca aggccacaaa cggaaatc  #                48 <210> SEQ ID NO 360 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 360ggattctaat acgactcact atagggctgt gctttcattc tgccagta  #                48 <210> SEQ ID NO 361 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 361ctatgaaatt aaccctcact aaagggaggg tacaattaag gggtggat  #                48 <210> SEQ ID NO 362 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 362ggattctaat acgactcact atagggcccg cctcgctcct gctcctg   #                47 <210> SEQ ID NO 363 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 363ctatgaaatt aaccctcact aaagggagga ttgccgcgac cctcacag  #                48 <210> SEQ ID NO 364 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 364ggattctaat acgactcact atagggcccc tcctgccttc cctgtcc   #                47 <210> SEQ ID NO 365 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 365ctatgaaatt aaccctcact aaagggagtg gtggccgcga ttatctgc  #                48 <210> SEQ ID NO 366 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 366ggattctaat acgactcact atagggcgca gcgatggcag cgatgagg  #                48 <210> SEQ ID NO 367 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 367ctatgaaatt aaccctcact aaagggacag acggggcaga gggagtg   #                47 <210> SEQ ID NO 368 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 368ggattctaat acgactcact atagggccag gaggcgtgag gagaaac   #                47 <210> SEQ ID NO 369 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 369ctatgaaatt aaccctcact aaagggaaag acatgtcatc gggagtgg  #                48 <210> SEQ ID NO 370 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 370ggattctaat acgactcact atagggccgg gtggaggtgg aacagaaa  #                48 <210> SEQ ID NO 371 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 371ctatgaaatt aaccctcact aaagggacac agacagagcc ccatacgc  #                48 <210> SEQ ID NO 372 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 372ggattctaat acgactcact atagggccag ggaaatccgg atgtctc   #                47 <210> SEQ ID NO 373 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 373ctatgaaatt aaccctcact aaagggagta aggggatgcc accgagta  #                48 <210> SEQ ID NO 374 <211> LENGTH: 47 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 374ggattctaat acgactcact atagggccag ctacccgcag gaggagg   #                47 <210> SEQ ID NO 375 <211> LENGTH: 48 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 375ctatgaaatt aaccctcact aaagggatcc caggtgatga ggtccaga  #                48 <210> SEQ ID NO 376 <211> LENGTH: 997<212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 376cccacgcgtc cgatcttacc aacaaaacac tcctgaggag aaagaaagag  #              50agggagggag agaaaaagag agagagagaa acaaaaaacc aaagagagag  #             100aaaaaatgaa ttcatctaaa tcatctgaaa cacaatgcac agagagagga  #             150tgcttctctt cccaaatgtt cttatggact gttgctggga tccccatcct  #             200atttctcagt gcctgtttca tcaccagatg tgttgtgaca tttcgcatct  #             250ttcaaacctg tgatgagaaa aagtttcagc tacctgagaa tttcacagag  #             300ctctcctgct acaattatgg atcaggttca gtcaagaatt gttgtccatt  #             350gaactgggaa tattttcaat ccagctgcta cttcttttct actgacacca  #             400tttcctgggc gttaagttta aagaactgct cagccatggg ggctcacctg  #             450gtggttatca actcacagga ggagcaggaa ttcctttcct acaagaaacc  #             500taaaatgaga gagtttttta ttggactgtc agaccaggtt gtcgagggtc  #             550agtggcaatg ggtggacggc acacctttga caaagtctct gagcttctgg  #             600gatgtagggg agcccaacaa catagctacc ctggaggact gtgccaccat  #             650gagagactct tcaaacccaa ggcaaaattg gaatgatgta acctgtttcc  #             700tcaattattt tcggatttgt gaaatggtag gaataaatcc tttgaacaaa  #             750ggaaaatctc tttaagaaca gaaggcacaa ctcaaatgtg taaagaagga  #             800agagcaagaa catggccaca cccaccgccc cacacgagaa atttgtgcgc  #             850tgaacttcaa aggacttcat aagtatttgt tactctgata caaataaaaa  #             900taagtagttt taaatgttaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa  #             950 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa   #               997 <210> SEQ ID NO 377 <211> LENGTH: 219<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 377Met Asn Ser Ser Lys Ser Ser Glu Thr Gln Cy #s Thr Glu Arg Gly  1               5  #                 10  #                 15Cys Phe Ser Ser Gln Met Phe Leu Trp Thr Va #l Ala Gly Ile Pro                 20  #                 25  #                 30Ile Leu Phe Leu Ser Ala Cys Phe Ile Thr Ar #g Cys Val Val Thr                 35  #                 40  #                 45Phe Arg Ile Phe Gln Thr Cys Asp Glu Lys Ly #s Phe Gln Leu Pro                 50  #                 55  #                 60Glu Asn Phe Thr Glu Leu Ser Cys Tyr Asn Ty #r Gly Ser Gly Ser                 65  #                 70  #                 75Val Lys Asn Cys Cys Pro Leu Asn Trp Glu Ty #r Phe Gln Ser Ser                 80  #                 85  #                 90Cys Tyr Phe Phe Ser Thr Asp Thr Ile Ser Tr #p Ala Leu Ser Leu                 95  #                100  #                105Lys Asn Cys Ser Ala Met Gly Ala His Leu Va #l Val Ile Asn Ser                110   #               115   #               120Gln Glu Glu Gln Glu Phe Leu Ser Tyr Lys Ly #s Pro Lys Met Arg                125   #               130   #               135Glu Phe Phe Ile Gly Leu Ser Asp Gln Val Va #l Glu Gly Gln Trp                140   #               145   #               150Gln Trp Val Asp Gly Thr Pro Leu Thr Lys Se #r Leu Ser Phe Trp                155   #               160   #               165Asp Val Gly Glu Pro Asn Asn Ile Ala Thr Le #u Glu Asp Cys Ala                170   #               175   #               180Thr Met Arg Asp Ser Ser Asn Pro Arg Gln As #n Trp Asn Asp Val                185   #               190   #               195Thr Cys Phe Leu Asn Tyr Phe Arg Ile Cys Gl #u Met Val Gly Ile                200   #               205   #               210Asn Pro Leu Asn Lys Gly Lys Ser Leu                 215<210> SEQ ID NO 378 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe<400> SEQUENCE: 378 ttcagcttct gggatgtagg g           #                   #                   #21 <210> SEQ ID NO 379<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr#obe <400> SEQUENCE: 379 tattcctacc atttcacaaa tccg          #                   #                24 <210> SEQ ID NO 380<211> LENGTH: 49 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 380ggaggactgt gccaccatga gagactcttc aaacccaagg caaaattgg  #               49 <210> SEQ ID NO 381 <211> LENGTH: 26 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe<400> SEQUENCE: 381 gcagattttg aggacagcca cctcca          #                   #              26 <210> SEQ ID NO 382<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 382 ggccttgcag acaaccgt             #                   #                   #  18 <210> SEQ ID NO 383<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 383 cagactgagg gagatccgag a           #                   #                   #21 <210> SEQ ID NO 384<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 384 cagctgccct tccccaacca            #                   #                   # 20 <210> SEQ ID NO 385<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 385 catcaagcgc ctctacca             #                   #                   #  18 <210> SEQ ID NO 386<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 386 cacaaactcg aactgcttct g           #                   #                   #21 <210> SEQ ID NO 387<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 387 gggccatcac agctccct             #                   #                   #  18 <210> SEQ ID NO 388<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 388 gggatgtggt gaacacagaa ca           #                   #                 22 <210> SEQ ID NO 389<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 389 tgccagctgc atgctgccag tt           #                   #                 22 <210> SEQ ID NO 390<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 390 cagaaggatg tcccgtggaa            #                   #                   # 20 <210> SEQ ID NO 391<211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 391 gccgctgtcc actgcag             #                   #                   #   17 <210> SEQ ID NO 392<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 392 gacggcatcc tcagggccac a           #                   #                   #21 <210> SEQ ID NO 393<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 393 atgtcctcca tgcccacgcg            #                   #                   # 20 <210> SEQ ID NO 394<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 394 gagtgcgaca tcgagagctt            #                   #                   # 20 <210> SEQ ID NO 395<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 395 ccgcagcctc agtgatga             #                   #                   #  18 <210> SEQ ID NO 396<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 396 gaagagcaca gctgcagatc c           #                   #                   #21 <210> SEQ ID NO 397<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 397 gaggtgtcct ggctttggta gt           #                   #                 22 <210> SEQ ID NO 398<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 398 cctctggcgc ccccactcaa            #                   #                   # 20 <210> SEQ ID NO 399<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 399 ccaggagagc tggcgatg             #                   #                   #  18 <210> SEQ ID NO 400<211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 400 gcaaattcag ggctcactag aga           #                   #                23 <210> SEQ ID NO 401<211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 401 cacagagcat ttgtccatca gcagttcag         #                   #            29 <210> SEQ ID NO 402 <211> LENGTH: 22<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe<400> SEQUENCE: 402 ggcagagact tccagtcact ga           #                   #                 22 <210> SEQ ID NO 403<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 403 gccaagggtg gtgttagata gg           #                   #                 22 <210> SEQ ID NO 404<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 404 caggccccct tgatctgtac ccca          #                   #                24 <210> SEQ ID NO 405<211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 405 gggacgtgct tctacaagaa cag           #                   #                23 <210> SEQ ID NO 406<211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 406 caggcttaca atgttatgat cagaca          #                   #              26 <210> SEQ ID NO 407<211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 407 tattcagagt tttccattgg cagtgccagt t        #                   #                   #  31 <210> SEQ ID NO 408<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 408 tctacatcag cctctctgcg c           #                   #                   #21 <210> SEQ ID NO 409<211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 409 cgatcttctc cacccaggag cgg           #                   #                23 <210> SEQ ID NO 410<211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 410 gccaggcctc acattcgt             #                   #                   #  18 <210> SEQ ID NO 411<211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 411 ctccctgaat ggcagcctga gca           #                   #                23 <210> SEQ ID NO 412<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 412 aggtgtttat taagggccta cgct          #                   #                24 <210> SEQ ID NO 413<211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 413 cagagcagag ggtgccttg             #                   #                   # 19 <210> SEQ ID NO 414<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 414 tggcggagtc ccctcttggc t           #                   #                   #21 <210> SEQ ID NO 415<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 415 ccctgtttcc ctatgcatca ct           #                   #                 22 <210> SEQ ID NO 416<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 416 tcaacccctg accctttcct a           #                   #                   #21 <210> SEQ ID NO 417<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 417 ggcaggggac aagccatctc tcct          #                   #                24 <210> SEQ ID NO 418<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 418 gggactgaac tgccagcttc            #                   #                   # 20 <210> SEQ ID NO 419<211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 419 gggccctaac ctcattacct tt           #                   #                 22 <210> SEQ ID NO 420<211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 420 tgtctgcctc agccccagga agg           #                   #                23 <210> SEQ ID NO 421<211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr#obe <400> SEQUENCE: 421 tctgtccacc atcttgcctt g           #                   #                   #21 <210> SEQ ID NO 422<211> LENGTH: 3554 <212> TYPE: DNA <213> ORGANISM: Homo Sapien<400> SEQUENCE: 422gggactacaa gccgcgccgc gctgccgctg gcccctcagc aaccctcgac  #              50atggcgctga ggcggccacc gcgactccgg ctctgcgctc ggctgcctga  #             100cttcttcctg ctgctgcttt tcaggggctg cctgataggg gctgtaaatc  #             150tcaaatccag caatcgaacc ccagtggtac aggaatttga aagtgtggaa  #             200ctgtcttgca tcattacgga ttcgcagaca agtgacccca ggatcgagtg  #             250gaagaaaatt caagatgaac aaaccacata tgtgtttttt gacaacaaaa  #             300ttcagggaga cttggcgggt cgtgcagaaa tactggggaa gacatccctg  #             350aagatctgga atgtgacacg gagagactca gccctttatc gctgtgaggt  #             400cgttgctcga aatgaccgca aggaaattga tgagattgtg atcgagttaa  #             450ctgtgcaagt gaagccagtg acccctgtct gtagagtgcc gaaggctgta  #             500ccagtaggca agatggcaac actgcactgc caggagagtg agggccaccc  #             550ccggcctcac tacagctggt atcgcaatga tgtaccactg cccacggatt  #             600ccagagccaa tcccagattt cgcaattctt ctttccactt aaactctgaa  #             650acaggcactt tggtgttcac tgctgttcac aaggacgact ctgggcagta  #             700ctactgcatt gcttccaatg acgcaggctc agccaggtgt gaggagcagg  #             750agatggaagt ctatgacctg aacattggcg gaattattgg gggggttctg  #             800gttgtccttg ctgtactggc cctgatcacg ttgggcatct gctgtgcata  #             850cagacgtggc tacttcatca acaataaaca ggatggagaa agttacaaga  #             900acccagggaa accagatgga gttaactaca tccgcactga cgaggagggc  #             950gacttcagac acaagtcatc gtttgtgatc tgagacccgc ggtgtggctg  #            1000agagcgcaca gagcgcacgt gcacatacct ctgctagaaa ctcctgtcaa  #            1050ggcagcgaga gctgatgcac tcggacagag ctagacactc attcagaagc  #            1100ttttcgtttt ggccaaagtt gaccactact cttcttactc taacaagcca  #            1150catgaataga agaattttcc tcaagatgga cccggtaaat ataaccacaa  #            1200ggaagcgaaa ctgggtgcgt tcactgagtt gggttcctaa tctgtttctg  #            1250gcctgattcc cgcatgagta ttagggtgat cttaaagagt ttgctcacgt  #            1300aaacgcccgt gctgggccct gtgaagccag catgttcacc actggtcgtt  #            1350cagcagccac gacagcacca tgtgagatgg cgaggtggct ggacagcacc  #            1400agcagcgcat cccggcggga acccagaaaa ggcttcttac acagcagcct  #            1450tacttcatcg gcccacagac accaccgcag tttcttctta aaggctctgc  #            1500tgatcggtgt tgcagtgtcc attgtggaga agctttttgg atcagcattt  #            1550tgtaaaaaca accaaaatca ggaaggtaaa ttggttgctg gaagagggat  #            1600cttgcctgag gaaccctgct tgtccaacag ggtgtcagga tttaaggaaa  #            1650accttcgtct taggctaagt ctgaaatggt actgaaatat gcttttctat  #            1700gggtcttgtt tattttataa aattttacat ctaaattttt gctaaggatg  #            1750tattttgatt attgaaaaga aaatttctat ttaaactgta aatatattgt  #            1800catacaatgt taaataacct atttttttaa aaaagttcaa cttaaggtag  #            1850aagttccaag ctactagtgt taaattggaa aatatcaata attaagagta  #            1900ttttacccaa ggaatcctct catggaagtt tactgtgatg ttccttttct  #            1950cacacaagtt ttagcctttt tcacaaggga actcatactg tctacacatc  #            2000agaccatagt tgcttaggaa acctttaaaa attccagtta agcaatgttg  #            2050aaatcagttt gcatctcttc aaaagaaacc tctcaggtta gctttgaact  #            2100gcctcttcct gagatgacta ggacagtctg tacccagagg ccacccagaa  #            2150gccctcagat gtacatacac agatgccagt cagctcctgg ggttgcgcca  #            2200ggcgcccccg ctctagctca ctgttgcctc gctgtctgcc aggaggccct  #            2250gccatccttg ggccctggca gtggctgtgt cccagtgagc tttactcacg  #            2300tggcccttgc ttcatccagc acagctctca ggtgggcact gcagggacac  #            2350tggtgtcttc catgtagcgt cccagctttg ggctcctgta acagacctct  #            2400ttttggttat ggatggctca caaaataggg cccccaatgc tatttttttt  #            2450ttttaagttt gtttaattat ttgttaagat tgtctaaggc caaaggcaat  #            2500tgcgaaatca agtctgtcaa gtacaataac atttttaaaa gaaaatggat  #            2550cccactgttc ctctttgcca cagagaaagc acccagacgc cacaggctct  #            2600gtcgcatttc aaaacaaacc atgatggagt ggcggccagt ccagcctttt  #            2650aaagaacgtc aggtggagca gccaggtgaa aggcctggcg gggaggaaag  #            2700tgaaacgcct gaatcaaaag cagttttcta attttgactt taaatttttc  #            2750atccgccgga gacactgctc ccatttgtgg ggggacatta gcaacatcac  #            2800tcagaagcct gtgttcttca agagcaggtg ttctcagcct cacatgccct  #            2850gccgtgctgg actcaggact gaagtgctgt aaagcaagga gctgctgaga  #            2900aggagcactc cactgtgtgc ctggagaatg gctctcacta ctcaccttgt  #            2950ctttcagctt ccagtgtctt gggtttttta tactttgaca gctttttttt  #            3000aattgcatac atgagactgt gttgactttt tttagttatg tgaaacactt  #            3050tgccgcaggc cgcctggcag aggcaggaaa tgctccagca gtggctcagt  #            3100gctccctggt gtctgctgca tggcatcctg gatgcttagc atgcaagttc  #            3150cctccatcat tgccaccttg gtagagaggg atggctcccc accctcagcg  #            3200ttggggattc acgctccagc ctccttcttg gttgtcatag tgatagggta  #            3250gccttattgc cccctcttct tataccctaa aaccttctac actagtgcca  #            3300tgggaaccag gtctgaaaaa gtagagagaa gtgaaagtag agtctgggaa  #            3350gtagctgcct ataactgaga ctagacggaa aaggaatact cgtgtatttt  #            3400aagatatgaa tgtgactcaa gactcgaggc cgatacgagg ctgtgattct  #            3450gcctttggat ggatgttgct gtacacagat gctacagact tgtactaaca  #            3500caccgtaatt tggcatttgt ttaacctcat ttataaaagc ttcaaaaaaa  #            3550 ccca                  #                  #                   #           3554 <210> SEQ ID NO 423<211> LENGTH: 310 <212> TYPE: PRT <213> ORGANISM: Homo Sapien<400> SEQUENCE: 423 Met Ala Leu Arg Arg Pro Pro Arg Leu Arg Le#u Cys Ala Arg Leu   1               5  #                 10 #                 15 Pro Asp Phe Phe Leu Leu Leu Leu Phe Arg Gl#y Cys Leu Ile Gly                  20  #                 25 #                 30 Ala Val Asn Leu Lys Ser Ser Asn Arg Thr Pr#o Val Val Gln Glu                  35  #                 40 #                 45 Phe Glu Ser Val Glu Leu Ser Cys Ile Ile Th#r Asp Ser Gln Thr                  50  #                 55 #                 60 Ser Asp Pro Arg Ile Glu Trp Lys Lys Ile Gl#n Asp Glu Gln Thr                  65  #                 70 #                 75 Thr Tyr Val Phe Phe Asp Asn Lys Ile Gln Gl#y Asp Leu Ala Gly                  80  #                 85 #                 90 Arg Ala Glu Ile Leu Gly Lys Thr Ser Leu Ly#s Ile Trp Asn Val                  95  #                100 #                105 Thr Arg Arg Asp Ser Ala Leu Tyr Arg Cys Gl#u Val Val Ala Arg                 110   #               115  #               120 Asn Asp Arg Lys Glu Ile Asp Glu Ile Val Il#e Glu Leu Thr Val                 125   #               130  #               135 Gln Val Lys Pro Val Thr Pro Val Cys Arg Va#l Pro Lys Ala Val                 140   #               145  #               150 Pro Val Gly Lys Met Ala Thr Leu His Cys Gl#n Glu Ser Glu Gly                 155   #               160  #               165 His Pro Arg Pro His Tyr Ser Trp Tyr Arg As#n Asp Val Pro Leu                 170   #               175  #               180 Pro Thr Asp Ser Arg Ala Asn Pro Arg Phe Ar#g Asn Ser Ser Phe                 185   #               190  #               195 His Leu Asn Ser Glu Thr Gly Thr Leu Val Ph#e Thr Ala Val His                 200   #               205  #               210 Lys Asp Asp Ser Gly Gln Tyr Tyr Cys Ile Al#a Ser Asn Asp Ala                 215   #               220  #               225 Gly Ser Ala Arg Cys Glu Glu Gln Glu Met Gl#u Val Tyr Asp Leu                 230   #               235  #               240 Asn Ile Gly Gly Ile Ile Gly Gly Val Leu Va#l Val Leu Ala Val                 245   #               250  #               255 Leu Ala Leu Ile Thr Leu Gly Ile Cys Cys Al#a Tyr Arg Arg Gly                 260   #               265  #               270 Tyr Phe Ile Asn Asn Lys Gln Asp Gly Glu Se#r Tyr Lys Asn Pro                 275   #               280  #               285 Gly Lys Pro Asp Gly Val Asn Tyr Ile Arg Th#r Asp Glu Glu Gly                 290   #               295  #               300 Asp Phe Arg His Lys Ser Ser Phe Val Ile                305   #               310

What is claimed is:
 1. An isolated nucleic acid encoding a polypeptide having at least 80% sequence identity to: (a) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO: 132), lacking its associated signal peptide; (c) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (d) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation.
 2. The isolated nucleic acid of claim 1 encoding a polypeptide having at least 85% sequence identity to: (a) amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO: 132), lacking its associated signal peptide; (c) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (d) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation.
 3. The isolated nucleic acid of claim 1 encoding a polypeptide having at least 90% sequence identity to: (a) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID) NO:132); (b) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide; (c) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (d) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation.
 4. The isolated nucleic acid of claim 1 encoding a polypeptide having at least 95% sequence identity to: (a) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide; (c) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (d) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation.
 5. The isolated nucleic acid of claim 1 encoding a polypeptide having at least 99% sequence identity to: (a) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) the amino acid sequence of the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide; (c) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (d) the amino acid sequence of the polypeptide encoded by the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation.
 6. An isolated nucleic acid comprising: (a) a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide; (c) the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (e) the full-length coding sequence of the cDNA deposited under ATCC accession number
 209251. 7. The isolated nucleic acid of claim 6 comprising a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132).
 8. The isolated nucleic acid of claim 6 comprising a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide.
 9. The isolated nucleic acid of claim 6 comprising the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131).
 10. The isolated nucleic acid of claim 6 comprising the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131).
 11. The isolated nucleic acid of claim 6 comprising the full-length coding sequence of the cDNA deposited under ATCC accession number
 209251. 12. An isolated nucleic acid that hybridizes under stringent conditions to: (a) a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132); (b) a nucleic acid sequence encoding the polypeptide shown in FIG. 48 (SEQ ID NO:132), lacking its associated signal peptide; (c) the nucleic acid sequence shown in FIG. 47 (SEQ lID NO:131); (d) the full-length coding sequence of the nucleic acid sequence shown in FIG. 47 (SEQ ID NO:131); or (e) the full-length coding sequence of the cDNA deposited under ATCC accession number 209251, wherein the encoded polypeptide is capable of inducing chondrocyte redifferentiation; and further, wherein said stringent conditions employ hybridization using 50% formamide, 5×SSC, 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate. 5×Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., and washes at 42° C. in 0.2×SSC, at 55° C. in 50% formamide followed by a high-stringency wash at 55° C. in 0.1×SSC, EDTA.
 13. The isolated nucleic acid of claim 12 which is at least 10 nucleotides in length.
 14. A vector comprising the nucleic acid of claim
 1. 15. The vector of claim 14, wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.
 16. A host cell in vitro comprising the vector of claim
 14. 17. The host cell of claim 16, wherein said cell is a CHO cell, an E. coli or a yeast cell. 